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Item 1. Business

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We are a clinical-stage C lustered R egularly I nterspaced S hort P alindromic R epeats (“CRISPR”) genome-editing biopharmaceutical company dedicated to developing transformative therapies for patients with devastating diseases.

Our genome-editing platform, including our novel chRDNA ( C RISPR h ybrid R NA- DNA , or “chRDNA,” pronounced “chardonnay”) technology, enables more precise genome editing to develop cell therapies that are armored to improve activity against diseases.

We are advancing a pipeline of allogeneic, or off-the-shelf, cell therapies from our chimeric antigen receptor (“CAR”) -T (“CAR-T”) cell and CAR-natural killer (“CAR-NK”) cell platforms as readily available therapeutic treatments for patients.

We are initially focused on advancing our allogeneic cell therapies for the treatment of hematologic malignancies.

Our therapies are directed at established cell surface targets for which autologous CAR-T cell therapeutics have already demonstrated clinical proof of concept, including CD19 and B cell maturation antigen (“BCMA”), as well as targets such as C-type lectin-like molecule-1 (“CLL-1,” also known as CD371).

Our genome-editing platform, including our novel chRDNA ( C RISPR h ybrid R NA- DNA , or “chRDNA,” pronounced “chardonnay”) technology, enables more precise genome editing of allogeneic cell therapies.

Our allogeneic chimeric antigen receptor (“CAR”) -T (“CAR-T”) cell therapy product candidates are manufactured in advance with cells from healthy donors, with the goal of enabling broad patient access, rapid patient treatment, and increased manufacturing scale.

Our allogeneic CAR-T cell therapy product candidates in clinical development are directed at established cell surface targets against which autologous CAR-T cell therapeutics have already demonstrated clinical proof of concept, including CD19 and B cell maturation antigen (“BCMA”), as well as targets such as C-type lectin-like molecule-1 (“CLL-1”).

We use our chRDNA technologies to armor our cell therapies through multiple genome-editing strategies, such as checkpoint disruption, immune cloaking, or a combination of these two strategies, to enhance activity against devastating diseases.

Our pipeline includes three clinical-stage allogeneic cell therapies from our CAR-T cell platform targeting the treatment of hematologic malignancies.

Our pipeline is shown below:

* Also known as CD371

We are developing a pipeline of three clinical-stage allogeneic CAR-T cell therapies for the treatment of hematologic malignancies.

Our lead product candidate, CB-010, is an allogeneic CAR-T cell therapy that is, to our knowledge, the first anti-CD19 allogeneic, or off-the-shelf, CAR-T cell therapy to be evaluated in patients with second-line relapsed or refractory large B cell lymphoma (“r/r LBCL”).

To our knowledge, CB-010 is also the first clinical-stage allogeneic anti-CD19 CAR-T cell therapy with programmed cell death protein 1 (“PD-1”) removed from the CAR-T cell surface by a genome-edited knockout of the PDCD1 gene.

We have demonstrated in preclinical models that the PD-1 knockout improved the durability of antitumor activity by disrupting a pathway that leads to rapid T cell exhaustion.

CB-010 has received regenerative medicine advanced therapy (“RMAT”) designation for r/r LBCL, fast track designation for relapsed or refractory B cell non-Hodgkin lymphoma (“r/r B-NHL”), and orphan drug designation for follicular lymphoma (“FL”) from the U.S.

We are advancing our pipeline of allogeneic CAR-T cell therapies with the following four clinical development programs targeting the treatment of hematologic malignancies and autoimmune diseases:

an allogeneic anti-CD19 CAR-T cell therapy, being evaluated in patients with relapsed or refractory B cell non-Hodgkin lymphoma (“r/r B-NHL”) in our ANTLER phase 1 clinical trial

also being evaluated in patients with lupus nephritis (“LN”) and in patients with extrarenal lupus (“ERL”) in our GALLOP phase 1 clinical trial

an allogeneic anti-BCMA CAR-T cell therapy, being evaluated in patients with relapsed or refractory multiple myeloma (“r/r MM”) in our CaMMouflage phase 1 clinical trial

an allogeneic anti-CLL-1 CAR-T cell therapy, being evaluated in patients with relapsed or refractory acute myeloid leukemia (“r/r AML”) in our AMpLify phase 1 clinical trial

CB-010 has received regenerative medicine advanced therapy (“RMAT”) designation for relapsed or refractory large B cell lymphoma (“r/r LBCL”) as well as fast track designations for r/r B-NHL and refractory systemic lupus erythematosus (“SLE”) from the U.S.

Food and Drug Administration (“FDA”);

CB-010 is being evaluated in our ongoing ANTLER phase 1 clinical trial in patients with r/r B-NHL.

In the dose escalation portion of our ANTLER clinical trial, 16 patients were enrolled and treated with a single dose of CB-010.

Three dose levels of CB-010 were evaluated:

dose level 1 (40x10 6 viable CAR-T cells, n=8), dose level 2 (80x10 6 viable CAR-T

cells, n=5), and dose level 3 (120x10 6 viable CAR-T cells, n=3).

CB-011 has received fast track designation for r/r MM from the FDA;

and CB-012 has received fast track designation for r/r AML from the FDA.

Allogeneic CAR-T Cell Therapies

Allogeneic, or off-the-shelf, CAR-T cell therapies offer several advantages over commercially available autologous CAR-T cell therapies, including broad patient access, rapid patient treatment, and increased manufacturing scale:

• Broad patient access:

Of every 10 patients with second-line relapsed or refractory diffuse large B cell lymphoma (“DLBCL”), only approximately two patients currently receive commercially available autologous CAR-T cell therapies.

Many patients cannot wait weeks to months for autologous CAR-T cell therapy or their T cells are too dysfunctional to manufacture their individual therapy.

With allogeneic CAR-T cell therapy, many more patients could be served as these cell therapies are manufactured in advance from healthy donor T cells, making them readily available off-the-shelf for rapid patient treatment.

Additionally, commercially available autologous CAR-T cell therapies are primarily available at academic centers of excellence in metropolitan areas where a patient’s cells can be removed for modification through apheresis versus in the community hospital setting where the vast majority of patients are treated.

Allogeneic CAR-T cell therapies can be administered in academic centers of excellence and, in the future, in appropriate community hospital settings, regardless of apheresis capabilities, suggesting broader patient access to treatment.

• Rapid patient treatment:

Commercially available autologous CAR-T cell therapies are manufactured from the patient’s own T cells and require weeks to months for manufacturing, product release, and delivery back to the patient for treatment.

Given the long wait time, more than 50% of patients who receive autologous CAR-T cells

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require bridging therapy, adding additional therapies to their treatment journey.

In addition, approximately 40% of patients with second line (“2L”) DLBCL are not able to wait for autologous CAR-T cell therapy.

With allogeneic CAR-T cell therapy, patients can begin treatment within days.

• Increased manufacturing scale:

For autologous CAR-T cell therapy, one manufacturing run yields one treatment for one patient, which cannot be further scaled.

There are a limited number of CAR-T cell treatment centers where apheresis capabilities are available, In addition, manufacturing failures can prevent a patient from receiving their treatment.

In contrast, our allogeneic CAR-T cell therapy product candidates are manufactured from cells from healthy donors, prepared in advance of treatment, and the number of doses per manufacturing run can be scaled for broad patient access.

Our CRISPR chRDNA Genome-Editing Technologies

Genome-editing technologies used to date have limited efficiency, specificity, and versatility for performing the multiple, precise genomic edits necessary for allogeneic CAR-T cell therapy manufacturing.

Our CRISPR chRDNA genome-editing technologies are designed to address these limitations and enable us to apply armoring strategies to enhance allogeneic CAR-T cell therapy activity against diseases.

Using our chRDNA genome-editing technologies, we have successfully demonstrated multiplex genome editing while maintaining genomic integrity.

Our allogeneic CAR-T cell therapy product candidates incorporate increasing numbers of genome edits, as shown in the figure below.

We believe this level of editing sophistication has the potential to unlock the broad potential of allogeneic cell therapies by:

• Enhancing the activity of allogeneic cell therapies for potentially durable activity :

Our chRDNA technologies enable us to apply tailored armoring strategies to our allogeneic CAR-T cells, including (i) checkpoint disruption, through the knockout of programmed cell death protein 1 (“PD-1”) to sustain the activity of CAR-T cells by disrupting a pathway that leads to CAR-T cell exhaustion;

(ii) immune cloaking of CAR-T cells to reduce rejection by the patient’s immune system;

and (iii) a combination of these two strategies.

• Improving the genomic integrity of our products:

We have observed that our cell therapy product candidates have significantly lower levels of off-target edits compared to those made using first-generation CRISPR-Cas9 genome editing, and we believe we make multiple edits while maintaining genomic integrity.

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We believe that our chRDNA genome-editing technologies have broad potential to generate cell and gene therapies in oncology, autoimmune diseases, and in additional therapeutic areas.

We own a robust worldwide patent portfolio protecting our Cas9 chRDNA and our Cas12a chRDNA compositions and genome-editing methods.

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We are focused on the development of our pipeline of allogeneic CAR-T cell therapies.

We are advancing four clinical-stage programs from our allogeneic CAR-T cell therapy platform targeting the treatment of hematologic malignancies and autoimmune diseases.

Our pipeline is shown below:

RMAT designation for r/r LBCL

fast track designation for r/r B-NHL

orphan drug designation for follicular lymphoma (“FL”)

4 CB-010:fast track designation for refractory SLE

fast track and orphan drug designations for r/r MM

fast track and orphan drug designations for r/r AML

CB-010 is an anti-CD19 allogeneic CAR-T cell therapy product candidate that is being evaluated in patients with r/r B-NHL in our ANTLER phase 1 clinical trial and in patients with LN and ERL in our GALLOP phase 1 clinical trial.

To our knowledge, CB-010 is the first clinical-stage allogeneic anti-CD19 CAR-T cell therapy with a genome-edited knockout of the PDCD1 gene to prevent PD-1 expression on the CAR-T cell surface.

In the dose escalation portion of our ANTLER phase 1 clinical trial, 16 patients with multiple subtypes of aggressive r/r B-NHL were enrolled and three dose levels of CB-010 were evaluated:

dose level 1 (40x10 6 viable CAR-T cells), dose level 2 (80x10 6 viable CAR-T cells), and dose level 3 (120x10 6 viable CAR-T cells).

Patients received a lymphodepletion regimen that included two chemotherapy agents, cyclophosphamide and fludarabine, which are generally used for lymphodepletion prior to autologous CAR-T cell therapy.

To ensure optimal engraftment of the allogeneic CB-010 cells, we used a deeper regimen of these chemotherapeutic agents, i.e., cyclophosphamide at 60 mg/kg/day for two days and then fludarabine at 25 mg/m 2 /day for five days, than is used with the commercially available autologous CAR-T cell therapies.

Lymphodepletion reduces the number of the patient’s immune cells and creates an inflammatory state that is required for the infused CAR-T cells to effectively expand and persist for disease activity.

Following dose escalation, we began the dose expansion portion of our ANTLER trial and enrolled 30 patients with 2L LBCL to treat this larger patient population earlier in the course of their disease.

During these portions of our ANTLER trial, patients who had received prior CD19-targeted therapies were excluded.

During dose expansion, dose level 2 (80x10 6 viable CAR-T cells) was selected as the recommended phase 2 dose (“RP2D”) for CB-010.

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At a poster presentation during the 2024 American Society of Clinical Oncology (“ASCO”) Annual Meeting in June 2024, we presented safety, efficacy, and translational data for the first 46 patients evaluated in our ANTLER phase 1 clinical trial after a single dose of CB-010.

CB-010 was generally well-tolerated with adverse events as expected for anti-CD19 CAR-T cell therapies.

Based on these encouraging dose escalation data, we are evaluating CB-010 in second-line LBCL patients in the dose expansion portion of our ongoing ANTLER trial to determine the recommended phase 2 dose (“RP2D”).

In the second quarter of 2024, we plan to present initial dose expansion data, the RP2D in second-line LBCL patients and emerging translational data from the ANTLER phase 1 clinical trial, as well as an updated timeline for the pivotal phase 3 trial initiation.

Our second product candidate, CB-011, is an allogeneic CAR-T cell therapy that is, to our knowledge, the first anti-BCMA CAR-T cell therapy incorporating an immune cloaking approach that includes both the removal of the endogenous beta-2 microglobulin (“B2M”) protein and insertion of a beta-2-microglobulin–human-leukocyte-antigen-E–peptide transgene (“B2M–HLA-E”).

This strategy is designed to reduce CAR-T cell rejection by both patient T cells and natural killer (“NK”) cells to potentially enable more durable antitumor activity.

CB-011 is being evaluated in our CaMMouflage phase 1 clinical trial in patients with relapsed or refractory multiple myeloma (“r/r MM”).

Dose level 1 (50x10 6 viable CAR-T cells, n=3) and dose level 2 (150x10 6 viable CAR-T cells, n=3) have cleared in our CaMMouflage clinical trial without any observed dose-limiting toxicities (“DLTs”), and we are currently enrolling patients at dose level 3 (450x10 6 viable CAR-T cells).

CB-011 has received fast track and orphan drug designations for r/r MM from the FDA.

We plan to present initial dose escalation data from our CaMMouflage clinical trial by year-end 2024.

The third product candidate from our CAR-T cell platform is CB-012, an allogeneic CAR-T cell therapy targeting CLL-1 (also known as CD371).

CB-012 is, to our knowledge, the first allogeneic CAR-T cell therapy with both checkpoint disruption and immune cloaking strategies, and its manufacture requires a total of five genome edits.

We believe that CLL-1 is an attractive target for acute myeloid leukemia (“AML”) due to its expression on myeloid cancer cells, its enrichment in leukemic stem cells, and its absence on hematopoietic stem cells (“HSCs”).

We have dosed the first patient in our AMpLify phase 1 clinical trial, which is evaluating CB-012 at dose level 1 (25x10 6 viable CAR-T cells) in patients with relapsed or refractory AML (“r/r AML”).

Additionally, we are developing our early research-stage allogeneic CAR-NK cell platform derived from genome-edited induced pluripotent stem cells (“iPSCs”).

We have multiple armoring strategies in development for our CAR-NK cell platform, including a Casitas B-Lineage lymphoma proto-oncogene-B (“ CBLB ”) gene knockout to enhance cell activity, IL-15/IL-15RA fusion gene insertion for enhanced cell persistence, and immune cloaking to reduce T cell-mediated rejection and to prevent NK cell fratricide (collectively, “NK cell self-killing”).

As part of our regular portfolio prioritization process, we have paused the development of CB-020, a ROR-1-targeted CAR-NK cell therapy product candidate for the treatment of solid tumors.

We are continuing to develop our CAR-NK cell platform and believe CAR-NK cells have potential for the treatment of multiple diseases.

Our CRISPR chRDNA Technologies

The genome-editing technologies currently used in the allogeneic cell therapy field generally have limited efficiency, specificity, and versatility for performing the multiple, precise genomic edits necessary to enhance efficacy and antitumor activity of these therapies.

Our chRDNA technologies are designed to address these genome-editing limitations and improve the antitumor activity in allogeneic cell therapies.

Our goal is to apply armoring strategies to our allogeneic cell therapies, which we believe could unlock their full potential by improving upon their effectiveness and antitumor activity.

We believe that our chRDNA technologies have broad potential to generate gene and cell therapies in oncology and in therapeutic areas beyond oncology.

Potential applications include immune cell therapies, cell therapies derived from genome-edited iPSCs, and in vivo genome-editing therapies.

We own a robust worldwide patent portfolio protecting our Cas9 and Cas12a chRDNA technologies.

Our team and our culture are critical to our mission to develop innovative, transformative therapies for patients with devastating diseases through our novel CRISPR chRDNA genome editing technology.

A retrospective analysis of all patient data demonstrated that patients who received a dose of CB-010 manufactured from a donor with at least four matching human leukocyte antigen (“HLA”) alleles (of 12 total alleles) with the patient (referred to as “partial HLA matching”) resulted in improved progression-free survival (“PFS’) compared to patients who received a single dose of CB-010 from a donor with fewer than four matching HLA alleles.

To confirm the partial HLA matching strategy, we are enrolling approximately 20 additional 2L LBCL patients in the ongoing ANTLER phase 1 clinical trial.

In addition, we are enrolling a proof-of-concept cohort of up to 10 patients in our ANTLER phase 1 clinical trial who have relapsed following any prior CD19-targeted therapy in this population of unmet need.

We have expanded our clinical development of CB-010 to include autoimmune diseases.

CB-010 holds the potential for deep depletion of disease-causing B cells, which could reset the immune system, leading to sustained drug-free remission.

In our ANTLER phase 1 clinical trial, following a single dose of CB-010, the depletion and recovery of patients’ B cells is on par with the duration of B cell aplasia reported in a recent case series in the literature.

We have initiated our multicenter, open-label GALLOP phase 1 clinical trial to evaluate a single infusion of CB-010 at the RP2D for oncology (80x10 6 viable CAR-T cells) but with a different lymphodepletion regimen, also incorporating partial HLA matching, in adult patients with LN and ERL.

CB-011 is an anti-BCMA allogeneic CAR-T cell therapy product candidate that is being evaluated in patients with r/r MM in our CaMMouflage phase 1 clinical trial.

To our knowledge, CB-011 is the first anti-BCMA CAR-T cell therapy incorporating an immune cloaking approach that includes both the removal of the endogenous beta-2 microglobulin (“B2M”) protein and insertion of a beta-2-microglobulin–human-leukocyte-antigen-E–peptide transgene (“B2M–HLA-E”).

This immune cloaking armoring strategy results in no endogenous class I HLA alleles expressed on the CAR-T cell surface.

This reduces the number of potential mismatched HLA alleles to six from 12, resulting in a reduced risk of rapid immunologic clearing of the CAR-T cells by the patient.

In the dose escalation portion of our CaMMouflage phase 1 clinical trial, dose level 1 (50x10 6 viable CAR-T cells), dose level 2 (150x10 6 viable CAR-T cells), dose level 3 (450x10 6 viable CAR-T cells), and dose level 4 (800x10 6 viable CAR-T cells) of CB-011 have cleared without any observed dose-limiting toxicities (“DLTs”).

We have implemented a deeper lymphodepletion regimen that includes an increased dose of cyclophosphamide (up from the original 300 mg/m 2 /day to 500 mg/m 2 /day together with the same fludarabine dose of 30 mg/m 2 /day for three days).

Dose level 3 (450x10 6 viable CAR-T cells) and dose level 4 (800x10 6 viable CAR-T cells) with the deeper lymphodepletion have cleared with no DLTs observed.

We are enrolling additional patients at multiple dose levels with the deeper lymphodepletion regimen in order to further define safety and efficacy and to determine a RP2D.

CB-012 is an allogeneic anti-CLL-1 CAR-T cell therapy product candidate that is being evaluated in patients with r/r AML in our AMpLify phase 1 clinical trial.

To our knowledge, CB-012 is the first allogeneic CAR-T cell therapy armored with both checkpoint disruption and immune cloaking strategies.

Patients in our AMpLify phase 1 clinical trial receive a lymphodepletion regimen prior to CAR-T cell infusion.

The lymphodepletion regimen includes two chemotherapy agents, cyclophosphamide (750 mg/m 2 /day) and fludarabine (30 mg/m 2 /day) for three days.

Patients then have two days of rest, followed by a single CB-012 dose on day zero.

In the dose escalation portion of our AMpLify phase 1 clinical trial, dose level 1 (25x10 6 viable CAR-T cells), dose level 2 (75x10 6 viable CAR-T cells), and dose level 3 (150x10 6 viable CAR-T cells) of CB-012 have cleared without any observed DLTs, and we are enrolling patients at dose level 4 (300x10 6 viable CAR-T cells).

In July 2024, we announced that we had discontinued preclinical research activities associated with our allogeneic CAR-natural killer (“NK”) cell therapy platform to focus resources on our allogeneic CAR-T cell therapy platform and to advance our four clinical programs for oncology and autoimmune diseases.

In addition to our CAR-T cell therapy programs, we are developing in vivo genome-editing capabilities.

Cas12a chRDNA guides may offer improved specificity compared to all-RNA guides for in vivo genome-editing applications.

We are using Cas12a chRDNA guides to optimize the Cas12a mRNA sequence and refine our lipid nanoparticle formulations with a goal of demonstrating functional gene disruptions in animal models.

Our initial research is in non-humanized mouse models to demonstrate genome-editing and gene correction capabilities.

In the future, we aim to take a human sequence target and perform disease-specific edits and demonstrate highly efficient editing across multiple clinically relevant targets to highlight the broad therapeutic potential of this platform.

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Our mission is to develop innovative, transformative therapies for patients with devastating diseases through our novel chRDNA genome-editing technologies.

Our overarching goal is to build an integrated company that discovers, develops, manufactures, and commercializes genome-edited cell therapies that have the potential to treat patients with significant unmet needs.

Our initial focus is on allogeneic CAR-T cell therapies for hematologic malignancies and autoimmune diseases, and our chRDNA technologies offer additional potential applications in the future.

Key components of our strategy include:

• Applying our chRDNA genome-editing technology to engineer allogeneic cell therapies from our CAR-T cell platform that have the potential for durable activity against multiple diseases.

Our chRDNA technologies enable us to design allogeneic cell therapies with the potential to achieve enhanced activity against diseased cells through the use of armoring strategies, including (i) checkpoint disruption, such as through a knockout of PD-1 to sustain the activity of CAR-T cells by disrupting a pathway that leads to CAR-T cell exhaustion;

(ii) immune cloaking of CAR-T cells to reduce rejection by the lymphoid compartment of a patient’s immune system;

and (iii) a combination of these strategies.

• Developing allogeneic CAR-T cell therapies against clinically validated targets to derisk our clinical programs.

CB-010, directed to the CD19 antigen, is being evaluated in our ANTLER phase 1 clinical trial in patients with r/r B-NHL and our GALLOP phase 1 clinical trial in patients with LN and ERL.

CB-011, directed to the BCMA antigen, is being evaluated in our CaMMouflage phase 1 clinical trial in patients with r/r MM.

These are the targets of several commercially available autologous CAR-T cell therapies, which reduces target risk as we evaluate the safety and efficacy of our allogeneic CAR-T cell therapies in our ongoing clinical trials.

• Developing allogeneic CAR-T cell therapies against additional targets for diseases with limited treatment options.

We are applying our Cas12a chRDNA platform and insights from our more advanced programs to design allogeneic CAR-T cell therapies against targets for which there are no commercially available autologous CAR-T cell therapies.

For example, CB-012, directed to the CLL-1 target, is being evaluated in our AMpLify phase 1 clinical trial in patients with r/r AML.

• Pursuing select applications of our technology and indications on our own and through strategic collaborations.

We believe that our technology has broad potential to generate cell therapies in oncology, autoimmune diseases, and additional therapeutic areas.

Potential applications include immune cell therapies and in vivo genome-editing therapies.

We may selectively pursue these indications and applications using our internal expertise or through strategic collaborations.

Our team and our culture are critical to our mission to develop innovative, transformative therapies for patients with devastating diseases through our novel CRISPR chRDNA genome-editing technologies.

Our mission-driven team includes leaders who have significant experience, including driving global clinical and regulatory strategies for commercially available autologous CAR-T cell therapies through all phases of development and pivotal trials, and some of the scientists who invented the chRDNA genome-editing technologies we use today in our programs and who continue to drive our future innovations.

We were founded in 2011 by globally-recognized pioneers in CRISPR genome editing and nucleic acid biology:

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Haurwitz, Ph.D., who has served as our president and chief executive officer since our formation.

Doudna and Jinek serve on our scientific advisory board (“SAB”), which also includes world experts in patient care, clinical trial development to support commercialization, immunotherapies, CAR-T cell development and microbiome

interactions, and NK cell biology.

Our team of employees includes some of the scientists who invented the technologies we use today in our research and product development and who continue to drive innovation.

Genome-Editing Landscape and Limitations

Genome editing is a class of technologies that facilitate making specific changes to deoxyribonucleic acid (“DNA”) sequences inside living cells.

Canonical genome editing occurs in two steps, as shown in figure 2 below.

Doudna and Jinek serve on our scientific advisory board (“SAB”), which also includes world experts in CAR-T cell development, immunotherapies, oncology, autoimmune diseases, patient care, and clinical trial development to support commercialization.

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Genome-Editing Background

Genome editing is a class of technologies that facilitate engineering specific changes to deoxyribonucleic acid (“DNA”) sequences inside living cells.

Genome editing can occur in two steps, as shown in the figure below.

In the first step, a double-stranded break (“DSB”) is made at the location of the genome where the edit is desired.

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NHEJ is an error-prone process in which the broken DNA ends are reattached.

During NHEJ, the cell typically inserts or deletes a few nucleotides at the DSB.

These insertions and deletions (“indels”) destroy the coding sequence for the targeted gene, resulting in the knockout of the targeted sequence.

During NHEJ, the cell typically inserts or deletes nucleotides at the DSB.

These insertions and deletions (“indels”) generally disrupt the coding sequence for the targeted gene, resulting in the knockout of the targeted sequence.

HDR, by contrast, is a more controlled repair system where the cell incorporates donor DNA delivered during the experiment into the DSB, resulting in the site-specific insertion of the provided DNA sequence.

Genome editing may be initiated by generating a DSB in chromosomal DNA at a desired location.

The cell will seal the break by an error-prone process called NHEJ, leading to the formation of indels, resulting in a site-specific gene knockout.

If a donor DNA template is provided to the cell during genome editing that encodes a gene of interest, a process called HDR will result in the insertion of the donor DNA in a site-specific manner.

There are several well-established genome-editing technologies being applied to generate immune cell therapies currently in preclinical research or clinical development, including zinc-finger nucleases (“ZFNs”), transcription activator-like effector nucleases (“TALENs”), and meganucleases, but each has limitations with respect to both agility and ability to generate site-specific gene insertions with high efficiency.

More recently, CRISPR genome-editing technology has been used for the generation of ex vivo immune cell therapeutics.

The canonical CRISPR system utilizes Cas9, an enzyme that can cut genomic DNA.

The canonical CRISPR system utilizes a CRISPR-associated (“Cas”) protein Cas9, which can cut genomic DNA.

Cas9 is targeted to a specific site in a genome by a guide ribonucleic acid (“RNA”).

One of the drawbacks of CRISPR-Cas9 genome editing is the occurrence of off-target editing, edits that occur at sites in the genome other than at the intended target site.

Off-target edits can alter an oncogene or tumor suppressor gene, impact the biology of the target cell, or have other negative consequences on therapeutic development.

One of the disadvantages of CRISPR-Cas9 genome editing is the occurrence of off-target editing, edits that occur at sites in the genome other than at the intended target site due to the ability of RNA guides to bind to DNA sequences similar to the target DNA sequence.

Off-target edits throughout the genome can alter an oncogene or tumor suppressor gene, impact the biology of the target cell, or have other negative consequences on therapeutic development.

Additionally, the simultaneous occurrence of both on-target and off-target edits may lead to genomic rearrangements, including chromosomal translocations, that may be problematic for immune cell therapeutics, especially for ones requiring multiple edits.

Our CRISPR Hybrid RNA-DNA (chRDNA) Technologies

We deploy a new, next-generation CRISPR genome-editing platform, our novel chRDNA technologies, which uses hybrid guides containing both RNA and DNA for editing genomic DNA, providing a powerful tool with the potential to expand the use of allogeneic cell therapies.

Our CRISPR chRDNA Technologies

We deploy a new, next-generation CRISPR genome-editing platform, our novel chRDNA technologies, which use hybrid guides containing both RNA and DNA for editing genomic DNA to engineer our allogeneic CAR-T cell therapies.

The presence of DNA in a chRDNA guide significantly improves editing specificity relative to an all-RNA guide.

The addition of DNA into the guide increases the fidelity by reducing the binding of the guide to the target sequence, thereby resulting in even less binding of the chRDNA guide to non-target sequences that may be similar to, but different from, the intended target sequence.

Our chRDNA technologies use the canonical Streptococcus pyogenes Cas9 protein or the Acidaminococcus sp .

Cas12a protein and a guide that is composed of a mixture of RNA and DNA nucleotides in both the region that interacts with the chromosomal target DNA and in the region that does not interact with the target DNA.

Like Cas9, Cas12a is a Cas protein used to edit genomic DNA site-specifically.

The advantages of our chRDNA technologies include:

• Specificity:

Our chRDNA guides mediate higher genome-editing specificity as compared to all-RNA guides.

Significantly fewer off-target events are observed using our chRDNA guides versus first-generation CRISPR-Cas9 or CRISPR-Cas12a systems using all-RNA guides.

The improved genome-editing

specificity from the use of our chRDNA guides leads to a high degree of editing specificity with lower levels of off-target events.

See figure 3 below.

The improved genome-editing specificity from the use of our chRDNA guides leads to a high degree of editing specificity with lower levels of off-target events.

Our chRDNA guides retain high affinity to edit a genome at the intended location;

however, these guides have lower affinity for potential off-target sites to reduce the likelihood of a genome edit at an unintended location.

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evaluated the integrity and performance of chRDNA guides by employing two unique assays, the SITE-Seq® assay and the VINE assay, on two genes known from the scientific literature to exhibit high rates of off-target editing with either the Cas9 or Cas12a protein and all-RNA guides.

All-RNA guides generated both robust on-target and off-target editing.

In contrast to the all-RNA guides, the chRDNA guides maintained robust on-target editing but induced minor to no detectable off-target editing.

We developed chRDNA guides that target the exact same genomic locations that achieve equivalent on-target editing compared to the all-RNA guides.

We published research in Molecular Cell , a peer-reviewed journal, on the mitigation of off-target editing using Cas9 chRDNAs (Donohoue, P.D.

et al., Molecular Cell 81, 3637–3649, September 2, 2021).

• High efficiency:

We achieve a high degree of on-target gene knockout and insertion efficiency, facilitating robust multiplex editing including multiple gene insertions.

For example, for CB-011, Cas12a chRDNA genome editing leads to >60% of manufacturing-scale T cells with all four intended edits, including two separate site-specific gene insertions.

See figure 4 below.

We achieve a high degree of on-target gene knockout and site-specific gene insertion efficiency, facilitating robust multiplex editing, including multiple gene insertions.

For example, Cas12a chRDNA genome editing used in generating CB-011 leads to approximately 76-80% gene insertion rates for two separate site-specific gene insertions, which represent both high and reproducible gene insertion rates, and greater than 60% of manufacturing-scale CAR-T cells have all four intended edits (two knockouts and two site-specific knock-ins).

Achieving high efficiency gene insertion is more challenging than achieving high efficiency gene knockout.

To insert genes into T cells with our chRDNA technology, we transduce the cells with adeno-associated virus serotype 6 (“AAV6”), which contains the DNA template of interest to facilitate the integration of the DNA into the double-stranded break generated by the Cas9 chRDNA complex or the Cas12a chRDNA complex via the HDR pathway.

Our chRDNA genome-editing technologies do not rely on lentiviral or retroviral genome-editing methods, which are used in commercially available autologous CAR-T cell therapies to insert the CAR gene randomly into the genome and which may increase the risk of genomic mutagenesis.

• Versatility :

Our chRDNA guides are compatible with, and offer utility across, multiple cell types.

Our chRDNA guides are compatible with, and offer utility across, multiple cell types, including but not limited to T cells, NK cells, and induced pluripotent stem cells (“iPSCs”).

• Simplicity :

Our chRDNA guides are manufactured via chemical synthesis using readily available technologies.

chRDNA guides significantly improve genome-editing specificity relative to all-RNA guides.

Cas12a chRDNA genome editing mediates high rates of site-specific gene insertion.

Cas12a chRDNA genome editing and adeno-associated virus serotype 6 (“AAV6”) transduction leads to >60% of manufacturing-scale engineered T cells with all 4 edits (2 gene inserts and 2 gene knockouts).

Our chRDNA Guides

Our chRDNA technologies use the canonical Streptococcus pyogenes Cas9 protein or the Acidaminococcus sp.

The presence of DNA in a chRDNA guide significantly improves editing specificity relative to an all-RNA guide.

Like Cas9, Cas12a is a CRISPR associated enzyme used to edit genomic DNA site-specifically.

See figures 5 and 6 below.

Our next-generation chRDNA guides are hybrid molecules that contain both RNA and DNA nucleotides.

They enable significantly improved specificity compared to first-generation all-RNA guides.

We use our novel chRDNA guides with Cas9 or Cas12a in the development of our allogeneic cell therapies.

Our chRDNA Guides:

Highly Specific On-Target Genome Editing

Our chRDNA guides mediate higher genome-editing specificity as compared to all-RNA guides.

Our chRDNA guides retain sufficiently high affinity to edit a genome at the intended location;

however these guides have sufficiently low affinity for potential off-target sites to reduce the likelihood of a genome edit at an unintended location.

We evaluated the integrity and performance of chRDNA guides by employing two unique assays, the SITE-Seq® assay and the VINE assay, on two genes known from the scientific literature to suffer from high rates of off-target editing with either the Cas9 or Cas12a protein.

As seen in figure 3 above, all-RNA guides generated both robust on-target and off-target editing.

We developed chRDNA guides that target the exact same genomic locations that achieve equivalent on-target editing compared to the all-RNA guides.

In contrast to the all-RNA guides, the chRDNA guides induce minor to no detectable off-target editing.

For any single genome edit, the chRDNA platform provides high specificity for use in our product candidates.

We have generated chRDNA guides for Cas9 and for Cas12a targeting multiple distinct locations in the human primary T cell genome that lead to high efficiency and high specificity editing.

We published an article in Molecular Cell , a peer-reviewed journal, on the mitigation of off-target editing using Cas9 chRDNAs (Donohoue, P.D.

, Molecular Cell 81, 3637–3649, September 2, 2021).

Figure 3 above shows the increased editing specificity with Cas9 and Cas12a chRDNA guides relative to all-RNA guides.

Our chRDNA Guides:

Achieve Equivalent, High Gene Knockout Efficiencies Compared to Conventional all-RNA Guides

The inclusion of DNA in our chRDNA guides does not impair their activity, and they achieve knockout efficiencies in human primary T cells with either the Cas9 or Cas12a protein that are equivalent to the knockout efficiencies achieved with all-RNA guides.

Our chRDNA Guides:

Cas12a chRDNA-Mediated Editing Drives High Efficiency Gene Insertions

One of the challenges in the genome-editing field is obtaining a high degree of site-specific gene insertion.

High efficiency gene knockout is achievable with a variety of genome-editing technologies, but achieving high efficiency gene insertion is more challenging.

Either Cas9 or Cas12a can be used to insert a new gene into a genome.

We use the combination of the Cas12a protein and our chRDNA guides to generate particularly high and reproducible gene insertion rates.

Gene insertion requires delivery of the new gene into the target cells.

To insert genes into T cells with our chRDNA technology, we transduce the cells with AAV6, which contains the DNA template of interest to facilitate the integration of the DNA into the double-stranded break generated by the Cas9 chRDNA complex or the Cas12a chRDNA complex via the HDR pathway.

As shown in figure 4 above, during full-scale current good manufacturing processes (“cGMP”) manufacturing of CB-011 carried out by a contract manufacturing organization (“CMO”), we observed that approximately 76-80% gene insertion rates were achieved in human primary T cells edited with Cas12a chRDNAs, a significant rate compared to other genome-editing platforms, resulting in >60% of the T cell population containing all four desired edits.

We demonstrated the insertion of a BCMA-specific CAR transgene, or Insert 1, into the TRAC locus by staining the edited T cells for the expression of the CAR following the knockout of the T cell receptor (“TCR”), via a TRAC knockout, and the insertion of the CAR transgene into the TRAC locus.

In the same T cells, we demonstrated the insertion of a B2M–HLA-E fusion gene, or Insert 2, into the B2M locus by staining the edited T cells for the expression of HLA-E following the knockout of all class I antigens via a B2M knockout and the insertion of the B2M–HLA-E fusion gene into the B2M locus.

Immune Cell Therapies

Immune cell therapies have emerged as a revolutionary and potentially curative treatment for multiple kinds of cancers.

The regulatory approval and commercialization of multiple first-generation CD19- and BCMA-directed autologous CAR-T cell products have laid the foundation and opened a path for the development of more advanced cell therapeutics, including CAR-T cell products with next-generation capabilities and approaches.

Among these approaches, allogeneic cell therapy is positioned to unlock the broad potential of immune cells as a leading therapeutic modality.

Expansion, trafficking, and sufficient antitumor activity of allogeneic CAR-T cells are critical to achieving long-term efficacy.

We believe that the genome-editing technologies currently utilized in the allogeneic cell therapy field have limited specificity, efficiency, and versatility for performing the multiplex editing necessary to address these challenges.

Within the immune system, white blood cells, such as T cells and NK cells, are responsible for defending the body against not only pathogens but also abnormal cells, including cancer cells.

Receptors on the surface of T cells enable them to recognize tumor cells and coordinate the activation of other cells in an immune response leading to the destruction of the cancerous cells.

However, in many cases, cancer-specific T cells are not present in sufficiently high numbers or do not have the appropriate tumor specificity in a patient to eliminate a tumor.

Autologous immune cell therapies, the most advanced of which use T cells, are a class of therapies in which immune cells are removed from a patient’s body and modified to express a CAR.

A CAR is an engineered molecule that, when present on the surface of an immune cell, enables the immune cell to recognize specific proteins, or antigens, that are present on the surface of other cells, including cancer cells.

To manufacture autologous CAR-T cell therapies, a cancer patient’s own T cells are modified to express a particular CAR, grown outside the patient’s body to expand their numbers, and then infused back into the same patient to recognize and destroy cancer cells in a targeted manner.

Allogeneic Cell Therapies

Despite the regulatory approvals and commercialization of autologous CAR-T cell therapies, several limitations have prevented autologous therapies from achieving the full potential of CAR-T cell products:

• Limited patient access.

Many patients are not eligible for autologous therapy because of the quality of their T cells or the lengthy vein-to-vein time.

• Bridging therapy often required.

Long wait times between the initial collection of the patient’s T cells and the return of the manufactured cells back to the patient may require bridging therapy, an additional line of therapy.

• Manufacturing constraints.

At present, there are a limited number of CAR-T cell centers and there are often insufficient manufacturing slots available to meet patient demand for autologous therapies.

In addition, autologous cell manufacturing is complex and lengthy, and there can be manufacturing failures.

The consequence of a manufacturing failure is that a patient might never receive their treatment.

• High production costs limit scalability.

Due to the personalized nature of autologous therapy, only one patient can be treated from each manufacturing run;

the supply chain logistics, including manufacturing and delivery, result in high costs with limited ability to scale.

• Variable potency .

Often a patient’s T cells may be damaged and weakened due to prior cancer treatments or the biology of their disease, which may lead to manufacturing failures or variable potency of the manufactured CAR-T cells with variability in clinical outcomes of the therapy.

Off-the-shelf, or allogeneic, versions of CAR-T cell therapies derived from healthy donors or stem cells are attractive options for several reasons.

• Off-the-shelf availability.

Allogeneic CAR-T cells are manufactured in advance, are stored in inventory, and are available immediately for eligible patients, which significantly shortens wait time whereas autologous CAR-T cell therapies require patients to undergo leukapheresis and then wait for their individual therapy to be manufactured.

• Broad patient access.

Allogeneic cell therapies derived from healthy donor cells have the potential to provide therapeutic options for patients who are ineligible for autologous CAR-T cell treatments due to the condition of their T cells or rate of disease progression.

• Bridging therapy not required.

Patients receiving autologous cell therapy may require bridging therapy to treat their cancer from the time their T cells are collected until their CAR-T cell therapy is manufactured and administered.

Patients receiving allogeneic cell therapy, however, do not have to wait for their CAR-T cell therapy to be manufactured and thus may avoid the potential need for bridging therapy.

• More efficient and scalable manufacturing.

Allogeneic approaches utilize cells from healthy donors or stem cells, resulting in a streamlined manufacturing process and enhanced scalability relative to autologous cell therapies where each patient requires their own batch of cell therapy.

• Healthy donor cells engineered with genome-editing strategies for enhanced activity against disease.

Allogeneic cell therapies are prone to rapid rejection by a patient’s immune system, thus limiting antitumor activity.

Donor-derived or stem cell-derived allogeneic cell therapies can be armored via one or multiple genome-editing strategies with the intent of enhancing activity against disease.

Key Components of our Strategy

Our mission is to develop innovative, transformative therapies for patients with devastating diseases through our novel chRDNA genome editing.

Our overarching goal is to build an integrated company that discovers, develops, manufactures, and commercializes genome-edited therapies that have the potential to treat patients with significant unmet needs.

Our initial focus is on allogeneic cell therapies for hematologic malignancies, and our chRDNA technologies offer broad potential applications longer-term.

Key components of our strategy include:

• Applying our chRDNA genome-editing technology to engineer allogeneic cell therapies from our CAR-T and CAR-NK platforms that have the potential for durable activity against disease.

Our chRDNA technologies enable us to design allogeneic cell therapies with the potential to achieve enhanced cell killing activity through the use of tailored armoring strategies, including (i) checkpoint disruption, such as through a knockout of PD-1 to sustain the initial activity of CAR-T cells by disrupting a pathway that leads to CAR-T cell exhaustion;

(ii) immune cloaking of CAR-T cells to reduce rejection by the patient’s immune system;

(iii) cytokine support to enhance antitumor activity;

and (iv) a combination of these strategies.

• Developing allogeneic CAR-T cell therapies against clinically proven targets for the treatment of hematologic malignancies.

CB-010 is being evaluated in our ANTLER phase 1 clinical trial in patients with r/r B-NHL, and CB-011 is being evaluated in our CaMMouflage phase 1 clinical trial in patients with r/r MM.

CB-010 is directed to the CD19 antigen and CB-011 is directed to the BCMA antigen.

These targets have been clinically proven in autologous CAR-T cell therapies that have received regulatory approvals, which reduces target risk as we evaluate the safety, antitumor activity, and duration of response of our clinical-stage allogeneic CAR-T cell therapies.

• Developing additional allogeneic CAR-T cell therapies against new targets for the treatment of hematologic malignancies.

Immune cell therapies have emerged as an exciting and powerful approach for difficult-to-treat

hematologic malignancies in patients with limited treatment options.

We are applying our chRDNA platform and insights from our more advanced programs to design allogeneic CAR-T cell therapies against targets, such as CLL-1, for diseases for which there are no approved autologous CAR-T cell therapies, such as AML.

Our CB-012 product candidate is directed to the CLL-1 target and is being evaluated in our AMpLify phase 1 clinical trial in patients with r/r AML.

• Developing our research-stage CAR-NK cell platform by leveraging our iPSC-derived NK cell (“iNK”) capabilities.

We believe NK cells are a promising cell type for disease treatment.

We have developed robust protocols to edit iPSCs and to differentiate and expand them into iNK cells.

• Reinforcing our leadership in CRISPR genome editing through strategic investments in our platform and new technologies.

Our company was founded by leaders in CRISPR biology and the core of our company is based on genome editing technologies protected by a robust IP portfolio.

We will continue to invest in these areas to maintain our prominence in the field and to develop therapies in which our genome edits confer potential benefits to patients.

• Further expanding patient access to cell therapies via selective strategic collaborations.

We plan to seek opportunities with select collaborators as appropriate to accelerate our ability to develop therapeutics to address significant unmet medical need.

• Pursuing potential indications both within and outside of oncology, selectively on our own and through strategic collaborations.

We believe that our technology has broad potential to generate gene and cell therapies in oncology and in therapeutic areas beyond oncology.

Potential applications include immune cell therapies and in vivo genome-editing therapies.

We aspire to maximize the value of our technologies and capabilities for patient benefit through internal investment and development and collaborations.

Multiplex Genome-Editing Strategy Using our chRDNA Technologies

Using our chRDNA genome-editing technologies, we have successfully demonstrated multiplex genome editing while maintaining genomic integrity.

We believe this level of editing sophistication has the potential to unlock the broad use of allogeneic cell therapies by:

• Increasing the antitumor activity of allogeneic cell therapies, thereby potentially achieving long-term efficacy:

Our chRDNA technologies enable us to apply tailored armoring strategies to our allogeneic CAR-T cells, including (i) checkpoint disruption, through the knockout of PD-1 to sustain the initial activity of CAR-T cells by disrupting a pathway that leads to CAR-T cell exhaustion, (ii) immune cloaking of CAR-T cells to reduce rejection by the patient’s immune system, and (iii) a combination of these two strategies.

See figure 7 below.

Our CB-010 preclinical mouse xenograft data demonstrate that the PD-1 knockout results in a significant survival advantage compared to conventional allogeneic CAR-T cells without a PD-1 knockout.

• Improving the genomic integrity of our products :

We have observed that our product candidates have significantly lower levels of off-target edits compared to those made with first-generation CRISPR-Cas9, and we believe we can make multiple edits while maintaining genomic integrity.

We employ multiple armoring strategies to engineer allogeneic CAR-T cell therapies with the potential for durable antitumor activity.

Engineering Enhanced Antitumor Activity is the Key to Unlocking the Full Potential of Allogeneic Cell Therapies

CAR-T cells will generally proliferate in response to antigen engagement via their respective CAR.

However, allogeneic CAR-T cells are rapidly rejected by a patient’s immune system due to their divergent donor-derived genetic profile.

We believe engineering CAR-T cells to achieve enhanced antitumor activity is necessary for the realization of the full potential of allogeneic cell therapies.

Our chRDNA guides are manufactured using standard, scalable solid-phase phosphoramidite chemistry.

Genome-Editing Strategies for Allogeneic CAR-T Cell Therapies

CAR-T cells will generally proliferate in response to antigen engagement via the specificity of their respective CAR.

However, allogeneic CAR-T cells are rapidly rejected by a patient’s immune system due to their divergent donor-derived genetic profile and cell surface HLA presentation.

We believe engineering CAR-T cells to achieve enhanced target cell killing activity is necessary for the realization of the full potential of allogeneic cell therapies.

Furthermore, development of an allogeneic CAR-T cell therapy requires genome editing to remove proteins from donor T cells that may recognize and attack a patient’s tissue that, without removal, would pose a risk of graft versus host disease (“GvHD”).

Our Approach:

Armoring Cell Therapies for Enhanced Antitumor Activity

We believe that engineering enhanced antitumor activity is the key to unlocking the full potential of allogeneic cell therapies.

Our strategies to improve CAR-T cell antitumor activity are three-fold:

(i) checkpoint disruption, through a knockout of PD-1 to sustain the antitumor activity of CAR-T cells by disrupting a pathway that leads to CAR-T cell exhaustion, (ii) immune cloaking the CAR-T cells to blunt rapid rejection by the patient’s immune system, and (iii) a combination of these two strategies.

Similar approaches may be used for our CAR-NK cell platform where improved targeting, CAR-NK cell survival, and enhancement of cell activity is thought to be key.

Checkpoint Disruption with PD-1 Knockout Strategy

One of the approaches we deploy to increase the antitumor activity of CAR-T cells is to remove PD-1 from the CAR-T cell surface.

The PD-1/PD-L1 pathway leads to rapid exhaustion of T cells.

This occurs when a T cell expressing PD-1 engages with another cell expressing PD-L1.

Tumor cells and the patient’s own cells can express PD-L1, leading to interaction with PD-1 and subsequent exhaustion of the CAR-T cells.

We use our chRDNA technology to knockout the PDCDI gene to eliminate PD-1 expression from the CAR-T cell surface, thereby preventing PD-1/PD-L1-mediated exhaustion.

We believe that knocking out PD-1 will maintain the CAR-T cells in a higher antitumor state for an extended period of time, and we believe this will result in greater initial tumor debulking in the patient.

To our knowledge, our CB-010 product candidate is the first allogeneic CAR-T cell therapy in a clinical study with a PD-1 knockout, and we believe the PD-1 knockout enhances the potential for durable antitumor response of an allogeneic CAR-T cell therapy.

One of the approaches we deploy to increase the activity of CAR-T cells is to remove PD-1 from the CAR-T cell surface.

Engagement of the PD-1/PD-L1 axis leads to rapid exhaustion of T cells.

This occurs when a T cell expressing PD-1 interacts with another cell expressing the ligand PD-L1.

Diseased cells and the patient’s own cells can express PD-L1, leading to interaction with PD-1 and subsequent exhaustion of the CAR-T cells.

We use our chRDNA technology to knock out the PDCD1 gene to prevent PD-1 expression on the CAR-T cell surface, thereby disrupting PD-1/PD-L1-mediated exhaustion.

We believe that knocking out PD-1 will maintain the CAR-T cells in a higher activity state for an extended period of time, and we believe this will result in greater diseased cell debulking in the patient.

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Immune-Cloaking Strategy

Another approach we deploy to increase the persistence of CAR-T cell antitumor activity is to immune cloak our CAR-T cells to reduce rapid immune-mediated rejection.

Another approach we deploy to increase the persistence of our CAR-T cells is to immune cloak them to reduce their rapid immune-mediated rejection.

The goal of immune cloaking is to maintain the allogeneic CAR-T cells in circulation for an extended period of time.

2 unchanged sentences

Our edits remove all endogenous HLA class I antigens from the CAR-T cell surface and lead to the overexpression of HLA-E, a minor HLA antigen, on the CAR-T cell surface.

The lack of endogenous HLA class I antigens and the presence of only HLA-E are

designed to prevent the patient’s T cells and NK cells from rapidly rejecting the allogeneic therapy.

The lack of endogenous HLA class I antigens and the presence of only HLA-E are designed to prevent the patient’s T cells and NK cells from rapidly rejecting the allogeneic therapy.

These cells are unlikely to persist indefinitely, and ultimately other types of immune cells in the patient will eliminate the allogeneic CAR-T cells.

Our edits are designed to maintain the CAR-T cells in circulation longer to enhance the antitumor response of the CAR-T cell therapy to destroy a larger proportion of the targeted tumor cells.

We use our novel chRDNA technologies to perform multiple genome edits to introduce armoring strategies intended to enhance antitumor activity and persistence of the cell therapy.

We are advancing a pipeline of three clinical-stage allogeneic CAR-T cell therapies focused on the treatment of hematologic malignancies.

Our pipeline is set forth in figure 9 below.

* Also known as CD371

We are developing a pipeline of three clinical-stage allogeneic CAR-T cell therapies for hematologic malignancies.

Our edits are designed to maintain the CAR-T cells in circulation longer to enhance the activity of the CAR-T cell therapy to destroy a larger proportion of the targeted cells.

Our Clinical Programs

We are advancing four clinical programs from our pipeline of allogeneic CAR-T cell therapies focused on the treatment of hematologic malignancies and autoimmune diseases.

Strategy and Rationale

Our lead product candidate is CB-010, a healthy donor-derived, genome-edited, allogeneic CAR-T cell therapy targeting CD19-positive malignancies, being evaluated in the ongoing first-in-human, open-label, multicenter ANTLER phase 1 clinical trial (NCT04637763) in the United States, Australia, and Israel in adults with r/r B-NHL.

CB-010 is designed to prevent rapid CAR-T cell exhaustion and confer a better therapeutic index compared to other allogeneic CAR-

T cell therapies.

To manufacture CB-010, we make three modifications to healthy donor-derived T cells using our Cas9 chRDNA genome-editing technology:

CB-010 has a PD-1 knockout for potentially enhanced activity against disease.

TRAC knockout:

We knock out the TRAC gene in order to eliminate expression of the TCR from the surface of the CAR-T cells.

The removal of TCR expression is intended to eliminate the risk of GvHD in patients.

Site-specific insertion of the anti-CD19 CAR:

We insert the CD19-targeted CAR into the TRAC gene by AAV6 transduction and HDR.

PD-1 knockout:

We knock out the PDCD1 gene, which encodes for PD-1, a checkpoint receptor, for enhanced antitumor activity, potentially leading to a better therapeutic index.

To our knowledge, CB-010 is the first allogeneic CAR-T cell therapy in the clinic with a PD-1 knockout.

Other CAR-T cell therapies that express endogenous PD-1 could become rapidly exhausted and lose antitumor activity due to the interaction between PD-1 and its ligand PD-L1.

The PD-1/PD-L1 pathway leads to rapid exhaustion in T cells.

This occurs when a T cell expressing PD-1 engages with another cell expressing PD-L1.

B cell tumors and the patient’s own cells can express PD-L1, leading to interaction with PD-1 and subsequent exhaustion of the CAR-T cells.

We eliminate PD-1 expression from the CB-010 CAR-T cells, thereby preventing PD-1/PD-L1-mediated exhaustion.

More than half of B-NHL tumors express PD-L1, and expression of PD-L1 in B-NHL correlates with poorer outcomes.

We believe that knocking out PD-1 will maintain the CAR-T cells in a higher antitumor state for an extended period of time, which we believe will result in greater initial tumor debulking in the patient, thereby enabling a potentially better therapeutic index relative to PD-1-expressing CAR-T cells.

Target Indication

We are developing CB-010 for the treatment of r/r B-NHL, with a focus on second-line LBCL.

NHL is the most common hematologic malignancy with an estimated 80,500 cases, or 4% of all cancers, diagnosed in the United States in 2023 according to the National Cancer Institute SEER database.

CB-010 is an allogeneic CAR-T cell therapy targeting CD19-positive hematologic malignancies and autoimmune diseases.

CB-010 is being evaluated in our ongoing first-in-human, open-label, multicenter ANTLER phase 1 clinical trial (NCT04637763) in the United States, Australia, and Israel in adults with r/r B-NHL as well as in our open-label, multicenter GALLOP phase 1 clinical trial (NCT06752876) in the United States in adults with LN and ERL.

To our knowledge, our CB-010 product candidate is the first allogeneic CAR-T cell therapy in a clinical trial with a PD-1 knockout, and we believe the PD-1 knockout enhances the potential for durable activity of an allogeneic CAR-T cell therapy.

Other CAR-T cell therapies that express endogenous PD-1 could become rapidly exhausted and lose activity due to the interaction between PD-1 and its ligand PD-L1.

PD-1/PD-L1 engagement leads to rapid exhaustion in T cells.

This occurs when a T cell expressing PD-1 interacts with another cell expressing PD-L1.

B cell tumors and the patient’s own cells express PD-L1, leading to interaction with PD-1 and subsequent exhaustion of the CAR-T cells.

We prevent PD-1 expression on the CB-010 CAR-T cells, thereby disrupting PD-1/PD-L1-mediated exhaustion.

More than half of B-NHL tumors express PD-L1, correlating with poorer outcomes.

We believe that knocking out PD-1 will maintain the CAR-T cells in an enhanced activity state for an extended period of time, which we believe will result in greater activity against disease in the patient, thereby enabling a potentially better therapeutic index relative to PD-1-expressing CAR-T cells.

CB-010 has received RMAT designation for r/r LBCL, fast track designations for r/r B-NHL and for refractory SLE, and orphan drug designation for FL from the FDA.

Target Indications

We are developing CB-010 for the treatment of r/r B-NHL, with a focus on 2L LBCL, as well as for the treatment of LN and ERL.

NHL is the most common hematologic malignancy with an estimated 80,620 individuals, or 4% of all cancers, diagnosed in the United States in 2024 according to the National Cancer Institute SEER database.

LBCL is a subtype of B-NHL and typically presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extranodal site.

LBCL subtypes include diffuse large B cell lymphoma not otherwise specified (“DLBCL NOS”), high-grade B cell lymphoma (“HGBL”), primary mediastinal large B cell lymphoma (“PMBCL”), transformed follicular lymphoma (“tFL”), and transformed marginal zone lymphoma (“tMZL”).

In 2022, approximately 10,000 second-line LBCL patients were newly diagnosed in the US.

The most common form of lymphoma is DLBCL, a type of LBCL, with approximately 25,000 patients diagnosed each year in the United States.

Overall, for aggressive r/r B-NHL, newer immunologically-mediated therapies under investigation include checkpoint inhibitors, bispecific antibodies, and CAR-T cells.

FDA-approved autologous CD19-specific CAR-T cell therapies have shown significant complete response rates, improved progression-free survival, and extended overall survival.

Despite the clinical benefits of these FDA-approved autologous CAR-T cell therapies, they are expensive and challenging to manufacture, and many patients are ineligible, cannot wait the long vein-to-vein time, and may require bridging therapy.

Commercially available autologous anti-CD19 CAR-T cell therapies have shown encouraging complete response (“CR”) rates, PFS, and overall survival;

however, there are many barriers, including limited patient access, length of time to treatment, and manufacturing capacity and scale limitations.

Thus, there remains a significant unmet medical need for patients with r/r B-NHL.

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LN and ERL are sub-categories of SLE, the most common form of lupus.

Lupus is a chronic autoimmune disease characterized by B cell dysfunction in which the immune system attacks the patient’s own tissues, causing widespread inflammation and organ damage.

There are over 200,000 individuals with SLE in the United States according to the Centers for Disease Control and Prevention.

It has been estimated that about 50% of patients with SLE will develop lupus nephritis and, of those, roughly 10-30% of patients will progress to end-stage renal disease, which requires dialysis or kidney transplant.

Treatments for lupus include antimalarials, steroids, non-steroidal anti-inflammatories, immunosuppressives, blood thinners, and monoclonal antibodies (“mAbs”), among others.

Investigational approaches such as autologous CAR-T cell therapies are being evaluated for lupus;

however, issues related to scale and access, as well as the need for a washout of lupus drugs prior to apheresis and cell therapy infusion, may present challenges due to an extended time in which the SLE disease may flare while the patients are taken off medications.

ANTLER Phase 1 Clinical Trial for CB-010 in r/r B-NHL

CB-010 is being evaluated in our ANTLER phase 1 clinical trial for the treatment of adult patients with aggressive forms of r/r B-NHL.

In dose escalation, CB-010 was evaluated in patients with several aggressive subtypes of r/r B-NHL, the majority of which were third-line or later.

In the ongoing dose expansion portion of ANTLER, CB-010 is being evaluated in second-line patients with LBCL.

To our knowledge, CB-010 is the first anti-CD19 allogeneic CAR-T cell therapy to be evaluated in the second-line LBCL setting.

Our ANTLER trial currently excludes patients who have previously received CD19-targeted therapy.

We are evaluating CB-010 in our ANTLER phase 1 clinical trial for the treatment of adult patients with aggressive forms of r/r B-NHL.

In dose escalation, CB-010 was evaluated in patients with several aggressive subtypes of r/r B-NHL, the majority of which were third-line or later treatments.

In the ongoing dose expansion portion of ANTLER, CB-010 is being evaluated in 2L LBCL patients.

Patients in our ANTLER phase 1 clinical trial receive a lymphodepletion regimen prior to CAR-T cell infusion.

The lymphodepletion regimen includes two chemotherapy agents, cyclophosphamide and fludarabine, which are generally used for lymphodepletion prior to autologous CAR-T cell therapy.

To ensure optimal engraftment of the allogeneic CB-010 cells, we use a more intensive regimen of these chemotherapeutic agents than is used with the commercially approved autologous CAR-T cell therapies, namely cyclophosphamide at 60 mg/kg/day for 2 days, then fludarabine at 25 mg/m 2 /day for 5 days.

The objectives of our ANTLER trial include the assessment of safety, including the incidence of DLT adverse events within 28 days after CB-010 infusion, as well as the overall objective response rate and the identification of the RP2D, as shown in figure 11 below.

Our ANTLER phase 1 clinical trial consists of two parts and we estimate enrolling up to approximately 60 patients across multiple centers in the United States and internationally.

Part A was a dose escalation following a standard 3 + 3 design, with sequential, increasing single doses of CB-010, and was completed with 16 patients dosed.

Part B is the dose expansion portion where CB-010 is evaluated to determine the RP2D in second-line LBCL patients.

The FDA granted CB-010 RMAT designation for r/r LBCL, fast track designation for r/r B-NHL, and orphan drug designation for FL.

To ensure optimal engraftment of the allogeneic CB-010 cells, we use a deeper regimen of these chemotherapeutic agents, i.e., cyclophosphamide at 60 mg/kg/day for two days and then fludarabine at 25 mg/m 2 /day for five days, than is used with the commercially available autologous CAR-T cell therapies.

The objective of our ongoing ANTLER phase 1 clinical trial is to further assess the safety and overall objective response rate (“ORR”) of CB-010 in r/r B-NHL patients at the RP2D and in patients who are receiving a partially HLA matched dose of CB-010.

Our ANTLER phase 1 clinical trial consists of two parts:

Part A was the dose escalation portion that followed a standard 3 + 3 design, with sequential, increasing single doses of CB-010, and was completed with 16 patients dosed at dose level 1 (40x10 6 viable CAR-T cells), dose level 2 (80x10 6 viable CAR-T cells), or dose level 3 (120x10 6 viable CAR-T cells).

Part B was the dose expansion portion where CB-010 was evaluated in larger numbers of patients to determine the RP2D in 2L LBCL patients.

Dose level 2 (80x10 6 viable CAR-T cells) was selected as the RP2D.

In these portions of our ANTLER trial, patients who had received prior CD19-targeted therapy were excluded.

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1 Subtypes include:

diffuse large B cell lymphoma (“DLBCL”), high-grade B cell lymphoma (“HGBL”), transformed DLBCL from FL (“tFL”), primary mediastinal large B cell lymphoma (“PMBCL”), FL (aggressively behaving with POD24 (high risk)), and marginal zone lymphoma (“MZL”).

DLBCL, HGBL, tFL PMBCL, MCL (mantle cell lymphoma), FL (follicular lymphoma, aggressively behaving with POD24 (high risk)), MZL (marginal zone lymphoma).

2 LBCL subtypes include:

2 unchanged sentences

doi:10.1158/1078-0432.CCR-11-0116.

4 Includes two backfill patients at dose level 1 and two backfill patients at dose level 2.

Our ANTLER phase 1 clinical trial is designed to evaluate CB-010 in r/r B-NHL patients.

The study consists of two parts:

Part A is a dose escalation with a 3 + 3 design, with sequential, increasing single doses in patients with r/r B-NHL.

Part B is the expansion portion where CB-010 is evaluated to determine the RP2D in second-line LBCL patients.

ANTLER Phase 1 Trial Clinical Data for CB-010

On July 13, 2023, we announced the following positive results of the long-term follow-up from the dose escalation portion of our ANTLER phase 1 trial.

1 Aggressively behaving, with disease progression within 24 months of front-line chemoimmunotherapy (POD24), which is high risk.

2 Primary refractory disease.

3 The three-month scan for patient 5 was conducted on day 63 post-CB-010 infusion, pursuant to the investigator’s discretion.

4 Patients 13-16 are backfill patients at the 40x10 6 cells and 80x10 6 cell doses.

5 Overall response rate (“ORR”).

Certain patients with initial complete response (“CR”) or partial response (“PR”) progressed to progressive disease (“PD”) at various assessment time points as indicated in the chart.

* Update on patient 4 presented at Lymphoma Leukemia & Myeloma Congress 2023;

CR is ongoing through month 21.

Results from the dose escalation portion of our ongoing ANTLER phase 1 clinical trial showed a 94% ORR (15 of 16 patients) following a single dose of CB-010;

69% of patients (11 of 16) achieved a CR;

and 44% of patients (7 of 16) had a CR at 6 months or after (24 months is the longest CR maintained to date).

( Data as of July 13, 2023, data collection ongoing, efficacy based on Lugano criteria .)

Safety results from patients at all three dose levels showed CB-010 was generally well-tolerated with adverse events (“AEs”) consistent with autologous or allogeneic anti-CD19 CAR-T cell therapies.

No grade 3+ cytokine release

syndrome (CRS) and no GvHD cases were observed.

The most common AEs included thrombocytopenia (69% grade 3+), neutropenia (56% grade 3+), and anemia (50% grade 3+).

See details in figure 13 below.

1 TEAEs are defined as adverse events (AEs) with a start date on or after the CB-010 infusion date.

2 Encephalopathy and grade 4 ICANS events were related and occurred in same patient.

Table includes AEs with at least two subjects at any single dose level or at least one subject with a higher than grade 3 TEAE.

(As of May 4, 2023 data cutoff date.)

Results from the dose escalation portion of our ongoing ANTLER phase 1 clinical trial show CB-010 was generally well-tolerated with such adverse events as are expected for anti-CD19 CAR-T cell therapies.

We are currently evaluating CB-010 in patients with second-line r/r LBCL in our ANTLER phase 1 clinical trial.

On December 12, 2023, we announced that we had received feedback from the FDA following a Type B clinical meeting and recent communications regarding CB-010.

The FDA provided feedback on a phase 3 randomized controlled trial for CB-010 for patients with r/r LBCL, stating that our proposed comparator arm of platinum-based immunochemotherapy followed by high dose chemotherapy and autologous stem cell transplantation is acceptable.

ANTLER Phase 1 Trial Clinical Data for CB-010 in r/r B-NHL

At a poster presentation during the ASCO annual meeting in June 2024, we presented safety, efficacy, and translational data for the first 46 patients evaluated in our ANTLER phase 1 clinical trial demonstrating safety and efficacy after a single dose of CB-010 with partial HLA matching.

A retrospective analysis of all patient data demonstrated that patients who received a dose of CB-010 manufactured from a donor with at least four HLA alleles matched resulted in improved PFS compared to patients who received a single dose of CB-010 from a donor with fewer than four HLA allele matched, as shown below.

confidence interval;

not estimable;

partial HLA matching:

patient has at least four HLA alleles that match

donor T cells used for CB-010 manufacturing.

* Retrospective analysis of HLA allele matching for class I and class II antigens.

ANTLER phase 1 clinical trial as of April 1, 2024, cutoff date;

data collection ongoing.

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At the 2024 ASCO annual meeting, translational research data on CB-010 were also presented, including pharmacokinetic (“PK”) and pharmacodynamic (“PD”) data.

PK data showed that higher numbers of matched HLA alleles between the CB-010 donor and recipient patient correlated with increased CAR-T cell expansion and persistence compared to lower numbers of matched HLA alleles.

PD data showed that a single dose of CB-010 resulted in extended B cell aplasia (~114 days) and a rapid recovery of the patient’s endogenous T and NK cells (approximately three weeks).

CB-010 was generally well tolerated with adverse events (“AEs”) as expected for anti-CD19 CAR-T cell therapies.

No grade 3+ cytokine release syndrome (“CRS”) and no GvHD cases were observed, and AEs of special interest are shown below.

immune effector cell–associated neurotoxicity syndrome;

not reported.

1 Prolonged cytopenias are defined as grade 3 or higher events lasting beyond 30 days following CB-010 infusion;

37/46 (80%) recovered from cytopenias to grade ≤2 by day 35 post CB-010 treatment.

2 Median time of onset was three days (range 0-22), and median duration was three days (range 1-19).

3 Infection events reported were on or after CB-010 infusion, with highest grade reported per patient;

median time of onset was eight days (range 0-279) and media duration was 14 days (range 1-239).

4 Median time of onset was 7.5 days (range 6-34), and median duration was two days (range 1-27).

5 Two grade 3 and one grade 4 ICANS;

all resolved with supportive care.

Median time of onset was eight days and median duration was two days.

ANTLER phase 1 clinical trial as of April 1, 2024, cutoff date;

data collection ongoing.

To confirm that the partial HLA matching strategy can improve outcomes in patients who receive a single dose of CB-010 from a donor with at least four HLA alleles matched, we are enrolling approximately 20 additional 2L LBCL patients in the ongoing ANTLER phase 1 clinical trial.

In addition, we are enrolling a proof-of-concept cohort of up to 10 patients who have relapsed following any prior CD19-targeted therapy in this population of unmet need.

GALLOP Phase 1 Clinical Trial for CB-010 in LN and ERL

We are evaluating CB-010 in our GALLOP Phase 1 trial for the treatment of adult patients with LN or ERL.

The objective of our GALLOP phase 1 clinical trial is to evaluate the safety, PK profile, and initial clinical activity of a single dose of CB-010 (80x10 6 viable CAR-T cells) following a lymphodepletion regimen of cyclophosphamide at 20mg/kg/day for two days and fludarabine at 25mg/m 2 /day for three days.

Patients are screened for donor-specific anti-HLA antibodies and administered CB-010 manufactured from a donor with partial HLA matching.

The primary endpoint is safety.

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lymphodepletion;

Systemic Lupus Erythematosus Disease Activity Index.

Strategy and Rationale

CB-011 is a healthy donor-derived, genome-edited, allogeneic CAR-T cell therapy targeting BCMA-positive malignancies that is being evaluated in the ongoing open-label, multicenter CaMMouflage phase 1 clinical trial (NCT05722418) in the United States in adults with r/r MM.

The CB-011 cells express a potent, humanized anti-BCMA CAR that exhibits better performance in preclinical in vivo antitumor activity assays compared to other anti-BCMA CARs

we evaluated.

We acquired a novel humanized scFv directed to BCMA that we use for the generation of the BCMA-specific CAR in CB-011.

We believe that the edits we make to immune cloak the product will maintain the CB-011 cells in the patient’s circulation longer.

We make four genome edits using the Cas12a chRDNA technology to manufacture CB-011 as shown in figure 14 below.

CB-011 is engineered with an immune cloaking strategy to potentially improve antitumor activity.

CB-011 has a BCMA-specific CAR insertion, a knockout of the TCR, an insertion of a B2M–HLA-E fusion protein, and a knockout of B2M.

TRAC knockout:

We knock out the TRAC gene to eliminate expression of the TCR from the surface of the CAR-T cells.

The removal of TCR expression is intended to prevent GvHD in patients.

Site-specific insertion of the humanized anti-BCMA CAR:

We insert the BCMA-targeted CAR into the TRAC gene by AAV6 transduction and homology-directed repair.

B2M knockout:

We knock out the B2M gene, which encodes for a protein necessary for the presentation of HLA class I molecules on the surface of a T cell.

The disruption of the B2M locus yields a cell product that does not express endogenous HLA class I molecules, limiting the ability of the patient’s cytotoxic CD8 + T cells to detect and reject the CAR-T cell therapy.

Site-specific insertion of a B2M–HLA-E fusion protein:

We site-specifically insert a transgene that fuses B2M, HLA-E, and a peptide by AAV6 transduction and homology-directed repair.

HLA-E is a minor class I antigen that interacts with NK cells.

This insertion, combined with the B2M gene knockout, yields a cell product that has only HLA-E, and no other class I antigens, on its surface.

The presence of only HLA-E is designed to prevent both the patient’s T cells and NK cells from rapidly rejecting the therapy.

Our CB-011 immune cloaking strategy is intended to reduce both T cell- and NK cell-mediated rejection.

Unmodified CAR-T cells, those that have intact HLA class I antigens, are subject to rejection by the patient’s cytotoxic T cells once the T cells recognize the allogeneic CAR-T cells as foreign.

This is mediated by the presentation of peptides by the CAR-T cells via their HLA class I antigens to the patient’s immune system that will recognize them as foreign since the CAR-T cells are derived from a non-familial healthy donor.

If we only knock out the B2M gene, thereby eliminating all HLA class I antigens, the cytotoxic T cells of the patient would no longer recognize the CAR-T cells as foreign.

However, the NK cells of the patient would detect the lack of HLA class I antigens, a concept known as “missing self,” which would unleash the activity of the NK cells, enabling them to destroy the allogeneic CAR-T cells.

We engineer the CB-011 CAR-T cells with the intent to protect them from rejection by both the patient’s cytotoxic T cells and NK cells by removing endogenous HLA class I antigen presentation through the knockout of the B2M gene and by inserting a B2M–HLA-E fusion transgene into the B2M locus.

We believe that this strategy will enable the CB-011 CAR-T cells to remain in circulation longer in patients to potentially provide durable antitumor activity.

CB-011 is an allogeneic CAR-T cell therapy targeting BCMA-positive malignancies that is being evaluated in our ongoing open-label, multicenter CaMMouflage phase 1 clinical trial (NCT05722418) in the United States in adults with r/r MM.

We acquired a novel humanized single-chain variable fragment (“scFv”) directed to BCMA that we use for the generation of the BCMA-specific CAR in CB-011.

To our knowledge, CB-011 is the first anti-BCMA CAR-T cell therapy incorporating an immune cloaking approach that includes both the removal of the endogenous B2M protein and insertion of a B2M–HLA-E peptide transgene.

This immune cloaking armoring strategy results in no endogenous class I HLA alleles expressed on the CAR-T cell surface.

This reduces the number of potential mismatched HLA alleles to six from 12, resulting in a reduced risk of rapid immunologic clearing of the CAR-T cells by the patient.

CB-011 has received fast track and orphan drug designations for r/r MM from the FDA.

Target Indication

We are developing CB-011 for the treatment of r/r MM.

In 2023, 1.8% of all cancers were MM.

In 2024, 1.8% of all cancers were MM in the United States according to the National Cancer Institute SEER database.

The median age of diagnosis is 69 years, and there were an estimated 35,780 new cases in 2024 in the United States with an estimated 12,540 deaths in 2024.

Five-year survival in these patients is approximately 61%.

There has been significant interest in and activity against BCMA as a target over the past few years with the regulatory approval of two new autologous CAR-T cell therapy products and a bispecific antibody targeting BCMA.

Despite the clinical benefits of commercial autologous CAR-T cell therapies, they are expensive and challenging to manufacture, and many patients are ineligible;

bispecific antibodies require patients to receive frequent treatments and are associated with high infection rates.

Additionally, many treatments for MM are multidrug regimens comprising varying routes of administration and/or convoluted dosing schedules;

There has been significant interest in and activity against BCMA as a target, and autologous CAR-T cell therapy products and bispecific antibodies targeting BCMA are commercially available.

Commercially available anti-BCMA autologous CAR-T cell therapies have shown encouraging CR rates, PFS, and overall survival;

however, there are many barriers, including limited patient access, length of time to treatment, and manufacturing capacity and scale limitations.

Of every 10 patients with r/r MM, only approximately one patient currently receives an autologous CAR-T cell therapy.

Commercially available bispecific antibodies require patients to receive frequent treatments and are associated with high infection rates.

Additionally, many treatments for r/r MM are multidrug regimens comprising varying routes of administration and/or complicated dosing schedules;

these regimens can be complex and burdensome for both patients and physicians.

The need for simplified dosing schedules remains.

Thus, although we expect that approvals of additional therapies may serve to partially mitigate the need for more treatment options in r/r MM, therapies that prolong the lives of r/r MM patients or delay disease progression, address simpler manufacturing, and streamline dosing schedules are critical to address the unmet medical need in patients with r/r MM.

Due to limited patient access and treatment burden, there is a need for an off-the-shelf, readily available, single dose treatment for patients with r/r MM.

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CaMMouflage Phase 1 Clinical Trial for CB-011 in r/r MM

1 unchanged sentence

These patients have a documented diagnosis of active MM according to International Myeloma Working Group diagnostic criteria.

The patient population includes individuals for whom three or more lines of therapy, including a proteosome inhibitor (“PI”), an immunomodulatory drug (“IMiD”), and an anti-CD38 antibody, have failed.

Patients who have received a BCMA-targeted therapy within the last three months and/or prior CAR-T cell therapy are excluded from the trial.

Patients in our CaMMouflage phase 1 clinical trial receive a chemotherapy regimen prior to CAR-T cell infusion.

The chemotherapy regimen includes two agents, cyclophosphamide (300 mg/m 2 /day) and fludarabine (30 mg/m 2 /day) for

three days, which are generally used for lymphodepletion in these doses prior to autologous CAR-T cell therapy.

CB-011 is infused two days after completion of lymphodepletion (on Day 0).

The objectives of the trial include the assessment of safety, including the incidence of adverse events defined as dose-limiting toxicities after CB-011 infusion, as well as the overall objective response rate and the identification of the maximum tolerated dose (“MTD”) and RP2D, as shown in figure 16 below.

In our CaMMouflage trial, dose level 1 (50x10 6 viable CAR-T cells, n=3) and dose level 2 (150x10 6 viable CAR-T cells, n=3) have cleared without any DLTs, and we are enrolling patients at dose level 3 (450x10 6 viable CAR-T cells) for the dose escalation portion of this trial.

CB-011 has received fast track and orphan drug designations for r/r MM from the FDA.

We plan to present initial dose escalation data from our CaMMouflage clinical trial by year-end 2024.

Our CaMMouflage phase 1 clinical trial is being conducted in two parts across multiple centers in the United States.

Part A is a dose escalation following a standard 3 + 3 design, with sequential, increasing single doses of CB-011.

Part B is the expansion portion where patients receive CB-011 at the dose levels determined in Part A to determine the RP2D.

The trial design also optionally permits the dosing of backfill patients at previously cleared dose levels.

Our CaMMouflage phase 1 clinical trial is designed to evaluate CB-011 in r/r MM patients.

The study consists of two parts:

Part A is a dose escalation with a 3 + 3 design, with sequential, increasing single doses.

Part B is an expansion portion where CB-011 will be evaluated at the dose levels determined in Part A.

The study also permits backfill patients at dose levels that were previously deemed safe.

Preclinical Data

To demonstrate that the B2M–HLA-E fusion protein protects CB-011 from NK-mediated cell killing, we established an in vitro study where NK cells were incubated with three different kinds of CAR-T cells:

CAR-T cells unmodified for HLA class I presentation, CAR-T cells lacking B2M, and CB-011 CAR-T cells lacking B2M and expressing the B2M–HLA-E fusion protein.

The results of this analysis are shown in the left panel of figure 17 below.

The unmodified CAR-T cells were subject to killing, or lysis, by the NK cells.

The knockout of B2M led to enhanced killing by the NK cells, demonstrating the “missing self” hypothesis.

Insertion of the B2M–HLA-E fusion transgene in the CB-011 cells protected them from NK cells more than the unmodified cells, indicating they could resist killing by NK cells, thereby suggesting the potential for longer circulation in patients.

We additionally established an in vitro study where CB-011 CAR-T cells and unmodified CAR-T cells where co-incubated in vitro with peripheral blood mononuclear cell (“PBMC”)-derived CD8 + T cells as described in the right panel in figure 17 below.

The CB-011 CAR-T cells were more resistant to PBMC-derived CD8 + T cell-mediated lysis than unmodified CAR-T cells.

*in vitro cytotoxicity measured 24 hours after co-incubation.

Our CB-011 in vitro data demonstrate that expression of the B2M–HLA-E fusion protein reduces NK cell-mediated lysis (left) and B2M knockout reduces T cell-mediated lysis (right).

We acquired a novel humanized scFv directed to BCMA that we use for the generation of the CB-011 CAR.

This scFv was selected based on long-term survival demonstrated in the literature and in our preclinical studies.

We constructed CARs using this and other anti-BCMA scFvs, and we evaluated the antitumor potential of CAR-T cells expressing these different CARs in mice bearing BCMA-positive tumors.

In the left panel of figure 18 below, we show an example of mouse xenograft data comparing CB-011 cells with CAR-T cells expressing an alternative BCMA CAR previously described in the literature and evaluated in multiple clinical trials.

CB-011 cells led to statistically significantly longer survival of the tumor-bearing mice compared to an alternative anti-BCMA CAR-T cell or vehicle.

In the right panel of figure 18 below, we also show an example of a mouse orthotopic MM tumor xenograft study demonstrating that a single dose of CB-011 led to statistically significant longer survival of tumor-bearing mice compared to a negative control (vehicle).

CB-011 led to statistically significant longer survival of tumor-bearing mice relative to alternative anti-BCMA CAR-T cells.

The left panel represents established subcutaneous MM tumor xenograft after a single dose CAR-T cell treatment, and the right panel represents established orthotopic MM tumor xenograft after a single dose CAR-T cell treatment.

The patient population includes individuals for whom three or more lines of therapy, including a proteasome inhibitor (“PI”), an immunomodulatory drug (“IMiD”), and an anti-CD38 antibody, have failed.

Patients who have received a BCMA-targeted therapy within the last three months are excluded from the trial.

Patients in our CaMMouflage phase 1 clinical trial receive a lymphodepletion regimen prior to CAR-T cell infusion.

The lymphodepletion regimen includes two chemotherapy agents, cyclophosphamide and fludarabine, which are generally used for lymphodepletion prior to autologous CAR-T cell therapy.

We began the clinical trial utilizing 300 mg/m 2 /day of cyclophosphamide and 30 mg/m 2 /day of fludarabine, each for a total of 3 days.

We have recently implemented a lymphodepletion regimen that includes a deeper dose of cyclophosphamide (increased from 300 to 500 mg/m 2 /day) together with the same fludarabine dose.

The objective of the ongoing CaMMouflage phase 1 clinical trial is to assess safety, including the incidence of AEs defined as DLTs after CB-011 infusion, identify a maximum tolerated dose (“MTD”), if appropriate, assess the ORR at active dose levels, and identify the RP2D.

Our CaMMouflage phase 1 clinical trial is being conducted in two parts:

Part A is dose escalation following a standard 3 + 3 design, with sequential, increasing single doses of CB-011 with the ability to add additional patients at safe dose levels to further evaluate activity and safety.

Part B is the expansion portion where patients receive CB-011 at the dose level(s) determined in Part A to determine the RP2D.

In the dose escalation portion of our CaMMouflage phase 1 trial, dose level 1 (50x10 6 viable CAR-T cells), dose level 2 (150x10 6 viable CAR-T cells), and dose level 3 (450x10 6 viable CAR-T cells) with the initial lymphodepletion have cleared with no DLTs observed.

Dose level 3 (450x10 6 viable CAR-T cells) and dose level 4 (800x10 6 viable CAR-T cells) with the deeper lymphodepletion have cleared with no DLTs observed.

We are enrolling additional patients at multiple dose levels with the deeper lymphodepletion regimen in order to further define safety and efficacy and to determine a RP2D.

1 LD regimen:

recommended dose for expansion.

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Strategy and Rationale

CB-012 is a healthy donor-derived, genome-edited, allogeneic CAR-T cell therapy targeting CLL-1, a receptor expressed on AML tumor cells.

We are evaluating CB-012 in the ongoing first-in-human, open label, multicenter AMpLify phase 1 clinical trial (NCT06128044) in the United States.

We believe CLL-1 is a compelling target for the treatment of AML as it is expressed on >90% of AML tumors and leukemic stem cells, but not expressed on HSCs.

CB-012 is an allogeneic CAR-T cell therapy targeting CLL-1 that is being evaluated in the ongoing first-in-human, open-label, multicenter AMpLify phase 1 clinical trial (NCT06128044) in the United States in adults with r/r AML.

We have exclusively licensed, in the field of allogeneic cell therapy, the fully human scFv targeting CLL-1 used in CB-012 from Memorial Sloan Kettering Cancer Center (“MSKCC”).

We believe CLL-1 is a compelling target for the treatment of AML due to its expression on myeloid cancer cells, its enrichment in leukemic stem cells, and its absence on hematopoietic stem cells (“HSCs”).

The absence of expression on HSCs indicates that these bone marrow cells will not be targeted by the CLL-1-directed CB-012 CAR-T cells, thereby preventing a patient from loss of a critical compartment of their immune system vital to generating immune cells required for fighting infections and cancer.

As such, patients receiving CB-012 treatment should not require an HSC transplant to provide them with myeloid compartment cells for sustained immunity.

We have exclusively in-licensed from Memorial Sloan Kettering Cancer Center (“MSKCC”) in the field of allogeneic CLL-1-targeted cell therapy a panel of fully human scFvs targeting CLL-1, from which we have selected an appropriate scFv for the generation of our CAR.

As described above for CB-010 and CB-011, an important aspect of CB-012 is appropriately armoring the CAR-T cells using our Cas12a chRDNA technology to improve the persistence of antitumor activity.

We make multiple edits to CB-012 using our Cas12a chRDNA technology to enhance its antitumor activity.

We edit CB-012 with two armoring strategies, checkpoint disruption (used in CB-010) and immune cloaking (used in CB-011), by implementing five genome edits using our Cas12a chRDNA technology.

To our knowledge, CB-012 is the first allogeneic CAR-T cell therapy with both checkpoint disruption, through a PD-1 knockout, and immune cloaking, through a

B2M knockout and B2M–HLA-E fusion protein insertion;

both armoring strategies are designed to improve antitumor activity.

CB-012 has both checkpoint disruption and immune cloaking armoring strategies, designed to potentially improve antitumor activity.

TRAC knockout:

We knock out the TRAC gene to eliminate expression of the TCR from the surface of the CAR-T cells.

The removal of TCR expression is intended to prevent GvHD in patients.

Human anti-CLL-1 CAR site-specifically inserted into the TRAC gene:

We insert the CLL-1-targeted CAR into the TRAC gene by AAV6 transduction and homology-directed repair.

The insertion of the CAR yields a cell product that exhibits CLL-1-specific cytotoxicity and eliminates random integration of the CAR transgene achieved via other engineering approaches.

PD-1 knockout:

We knock out the PDCD 1 gene, which encodes for PD-1, a checkpoint receptor, for enhanced antitumor activity, potentially leading to a better therapeutic index.

B2M gene knockout:

We knock out the B2M gene to reduce HLA class I presentation and T cell-medicated rejection.

B2M–HLA-E-peptide fusion transgene site-specifically inserted into the B2M gene:

We site-specifically insert a transgene that fuses B2M, HLA-E, and a peptide by AAV6 transduction and homology-directed repair.

HLA-E is a minor class I antigen that interacts with NK cells.

This insertion, combined with the B2M knockout, yields a cell product that has only HLA-E, and no other class I antigens, on its surface.

The presence of only HLA-E is designed to blunt NK cell-mediated rejection.

To our knowledge, CB-012 is the first allogeneic CAR-T cell therapy with both checkpoint disruption, through a PD-1 knockout, and immune cloaking, through a B2M knockout and B2M–HLA-E fusion protein insertion.

CB-012 has received fast track and orphan drug designations for r/r AML from the FDA.

Target Indication

Acute myeloid leukemia is a cancer of the bone marrow currently treated with chemotherapy, radiation, targeted therapies, and/or HSC transplant.

There were an estimated 20,380 new cases of AML in the United States in 2023.

AML is a cancer of the bone marrow currently treated with chemotherapy, radiation, targeted therapies, and/or HSC transplant.

There were an estimated 20,800 new cases of AML in the United States in 2024 according to the National Cancer Institute SEER database.

Five-year survival in these patients is 32%.

Intensive induction chemotherapy, known as 7 + 3, consisting of cytarabine and an anthracycline, is the most effective therapy for adults newly diagnosed with AML, although the treatment has significant associated toxicities.

Thus, there remains significant unmet need in the treatment of patients with AML.

There remains significant unmet need in the treatment of patients with AML.

AMpLify Phase 1 Clinical Trial for CB-012 in r/r AML

We have dosed the first patient in our AMpLify phase 1 clinical trial, which is evaluating CB-012 in adult patients with r/r AML.

We are evaluating CB-012 in our AMpLify phase 1 clinical trial in adult patients with r/r AML.

Our AMpLify clinical trial includes patients who have not responded to or relapsed after standard treatment and excludes patients who have been treated with more than three prior lines of therapy and patients with proliferative disease.

Patients with prior allogeneic or autologous cell therapies are allowed to participate in our AMpLify clinical trial.

Patients in our AMpLify phase 1 clinical trial receive a chemotherapy regimen prior to CAR-T cell infusion.

The chemotherapy regimen includes two agents, cyclophosphamide (750 mg/m 2 /day) and fludarabine (30 mg/m 2 /day) for three days.

Patients then have two days of rest, following by a single CB-012 dose on Day 0.

The objectives of the trial include the assessment of safety, including the incidence of AEs defined as DLTs, after CB-012 infusion, as well as the overall objective response rate and the identification of the MTD and/or recommended dose(s) for expansion (“RDE”) and RP2D, as shown in figure 20 below.

We are currently enrolling patients at dose level 1 (25x10 6 viable CAR-T cells) in our AMpLify clinical trial.

Our AMpLify phase 1 clinical trial is an open-label study being conducted in two parts across multiple centers in the United States.

Patients who received prior allogeneic stem cell transplant are allowed to participate in our AMpLify clinical trial.

Patients in our AMpLify phase 1 clinical trial receive a lymphodepletion regimen prior to CAR-T cell infusion.

The lymphodepletion regimen includes two chemotherapy agents, cyclophosphamide (750 mg/m 2 /day) and fludarabine (30 mg/m 2 /day) for three days.

Patients then have two days of rest, followed by a single CB-012 dose on day zero.

The objective of our ongoing AMpLify trial is to assess safety, including the incidence of AEs defined as DLTs after CB-012 infusion, identify an MTD, if appropriate, assess the overall ORR at active dose levels, and identify the RP2D.

Our AMpLify phase 1 clinical trial is an open-label study being conducted in two parts:

Part A is the dose escalation portion following a standard 3 + 3 design, with sequential, increasing single doses of CB-012.

Part B is the expansion portion where patients will receive CB-012 at the dose levels determined in Part A to determine the RP2D.

Stem cell transplant (“SCT”)

Our AMpLify phase 1 clinical trial is designed to evaluate CB-012 in r/r AML patients.

The study consists of two parts:

Part A is the dose escalation portion with a 3 + 3 design, with sequential, increasing single doses.

Part B is the expansion portion where CB-012 will be evaluated at the dose levels determined in Part A.

Preclinical Data

We evaluated CB-012 in preclinical animal models, which demonstrated CB-012 significantly reduced tumor burden and increased overall survival.

As shown in figure 21 below, in an AML xenograft model, a single dose of CB-012

significantly reduced an orthotopically-established tumor burden over a long duration compared to vehicle, or negative control, treatment.

We conducted orthotopic engraftment of an HL-60 CLL-1 expressing AML model in NOD SCID gamma (“NSG”) mice.

Results showed that a single dose of CB-012 significantly reduced tumor burden over a long duration compared to vehicle treatment in this AML xenograft model.

In a second model, we evaluated CLL-1-specific CB-012 CAR-T cells compared to equivalent CAR-T cells that lacked the PD-1 KO in a xenograft model of CLL-1+ PD-L1+ tumor cells to evaluate the impact of the PD-1 knockout in CB-012.

As shown in figure 22 below, the CLL-1-specific CB-012 CAR-T cells statistically significantly increased overall survival in the tumor-bearing mice compared to mice that received either control CAR-T cells expressing PD-1 or the vehicle control.

The genome edits we use to armor CB-012 may enhance persistence and yield greater antitumor activity.

We conducted orthotopic engraftment of a U937 CLL-1-expressing and PD-L1-expressing cell line in NSG mice.

Results demonstrated that the PD-1 knockout strategy in CB-012 increased overall survival compared to control CAR-T cells without the PD-1 knockout.

Our Early-Stage Research

CAR-NK Cell Therapies

We are conducting research on CAR-NK cells derived from edited iPSCs.

We have developed robust differentiation and expansion protocols to derive iNKs from iPSCs.

These protocols enable us to perform multiple, sophisticated genome edits to iPSCs and differentiate them into iNKs.

There are multiple advantages of using iPSCs.

They are amenable to higher numbers of genome-editing events than most primary cells.

A solitary clone isolated after genome editing will have all the intended edits.

This is distinct from the allogeneic CAR-T cell products derived from healthy donor leukapheresis, where a proportion, but not all, of the T cells in a batch contain all the intended edits.

This fully edited iPSC clonal line will then be differentiated into iNK cells and expanded for therapeutic use.

This platform may enable us to generate sophisticated, armored iNK cell therapies.

An outline of the multi-step iPSC to CAR-NK platform we developed is shown in figure 23 below.

We have developed protocols to edit iPSCs and then differentiate them into CAR-NK cells.

We are developing multiple armoring strategies for our CAR-NK cell platform.

In figure 24 below, we show that these strategies can lead to enhanced target cell killing activity and persistence, as well as immune cloaking of the cells, in in vitro and/or in vivo experiments, as presented at the 2022 American Association for Cancer Research and Japanese Cancer Association (AACR-JCA) Conference.

We demonstrated that iNK cells with a CBLB knockout exhibit significant enhancement in target cell killing activity compared to wild-type (“WT”) iNK cells in a solid tumor model, as shown in figure 24 below, left panel.

We demonstrated that membrane-bound IL-15/IL-15RA fusion (mbIL-15) engineered iNK cells demonstrate enhanced cytotoxicity against a solid tumor cell line (middle panel).

We also demonstrated that knockout of the B2M gene and insertion of the B2M–HLA-E fusion protein reduced both CD8 + T cell-mediated killing and NK cell self-killing (fratricide), as shown in figure 24 below, right panel.

We are developing multiple armoring strategies for our CAR-NK cell platform.

As part of our regular portfolio prioritization process, we have paused the development of CB-020, a ROR-1-targeted CAR-NK cell therapy product candidate for the treatment of solid tumors.

We are continuing to develop our CAR-NK cell platform and believe CAR-NK cells have potential for the treatment of multiple diseases.

Part B is the expansion portion where patients will receive CB-012 at the dose level(s) determined in Part A to determine the RP2D.

Tabl e of Contents

In the dose escalation portion of our AMpLify trial, dose level 1 (25x10 6 viable CAR-T cells), dose level 2 (75x10 6 viable CAR-T cells), and dose level 3 (150x10 6 viable CAR-T cells) have cleared with no DLTs observed, and we are enrolling patients at dose level 4 (300x10 6 viable CAR-T cells).

stem cell transplant.

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CB-012 Preclinical Data

We evaluated CB-012 in preclinical mouse models, which demonstrated that CB-012 significantly reduced tumor burden and increased overall survival.

As shown in the left graph below, in a CLL-1+ AML xenograft model, a single dose of CB-012 significantly reduced an orthotopically established tumor burden over a long duration compared to vehicle, or negative control, treatment.

In a second model, we evaluated CLL-1-specific CB-012 CAR-T cells compared to equivalent CAR-T cells that lacked the PD-1 knockout in a xenograft model of CLL-1+ PD-L1+ tumor cells to evaluate the impact of the PD-1 knockout in CB-012.

As shown in the right graph below, the CLL-1-specific CB-012 CAR-T cells statistically significantly increased overall survival in the tumor-bearing mice compared to mice that received either control CAR-T cells expressing PD-1 (cells engineered with the same edits of CB-012 except the PDCD1 KO) or the vehicle control.

Strategic Agreements

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If we and Pfizer do not reach an agreement with respect to a Grant of Program Rights within the 30-day period, then we may pursue negotiations and enter into an agreement with any third party.

If we and such third party do not reach agreement on the Grant of Program Rights within a specified time period, Pfizer’s right of first negotiation will be reinstated.

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and such third party do not reach agreement on the Grant of Program Rights within a specified time period, Pfizer’s right of first negotiation will be reinstated.

Under the Information Rights Agreement, we also agreed to grant Pfizer the right to designate one representative to serve on our SAB.

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Additionally, we agreed to provide Pfizer access to any preclinical or interim or final clinical data (including raw data) and results generated as part of the development program for a BCMA Product Candidate at the same time that we provide such data to a third party (other than to our service providers or the FDA or other regulatory authorities), subject to certain confidentiality exceptions.

On June 29, 2023, we and Pfizer also entered into a Voting Agreement, pursuant to which, for a period of 12 months, Pfizer agreed to cause our voting securities that Pfizer beneficially owns (within the meaning of Rules 13d-3 or 13d-5 under the Securities Exchange Act of 1934, as amended (“Exchange Act”)) in excess of 4.99% of our then issued and outstanding voting securities to be voted (i) with respect to any matter directly relating to remuneration of directors, directors’ insurance, or indemnification or release from liability of directors, in a manner proportionally consistent with the votes properly cast for and against by holders of voting securities not beneficially owned by Pfizer, and (ii) with respect to any other matter in which Pfizer shall have the right to vote such voting securities, in accordance with the recommendation of our board of directors or any applicable committee thereof.

Memorial Sloan Kettering Cancer Center

On November 13, 2020, we entered into an Exclusive License Agreement with MSKCC (“MSKCC Agreement”), under which we exclusively licensed from MSKCC know-how, biological materials, and related patent families to fully human scFvs targeting CLL-1 (also known as CD371) for use in T cells, NK cells, and genome-edited iPSCs for allogeneic CLL-1-targeted cell therapy.

On November 13, 2020, we entered into an Exclusive License Agreement with MSKCC (as amended, “MSKCC Agreement”), under which we exclusively licensed from MSKCC know-how, biological materials, and related patent families to fully human scFvs targeting CLL-1 (also known as CD371) for use in T cells, NK cells, and genome-edited iPSCs for allogeneic CLL-1-targeted cell therapy.

We use one of the licensed scFvs in our CB-012 product candidate.

We paid an upfront payment of cash and shares of our common stock and will owe annual license maintenance fees until we have commercial sales.

For each licensed CLL-1 product, we will owe potential clinical, regulatory, and commercial milestone payments totaling up to $112.0 million and, if we, or our affiliates or sublicensees, receive regulatory approval for a licensed CLL-1 product, we will owe low- to mid-single-digit percent royalties on net sales by us, our affiliates, and our sublicensees.

For each licensed CLL-1 product, we will owe potential clinical, regulatory, and commercial milestone payments totaling up to $111.0 million and, if regulatory approval for a licensed CLL-1 product is received, we will owe low- to mid-single-digit percent royalties on net sales of licensed products.

Our license includes the right to sublicense through multiple tiers and we will owe MSKCC a percentage of upfront cash or equity received from our sublicensees.

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The MSKCC Agreement includes certain diligence milestones that we must meet;

provided, however, that these may be extended upon payment of additional fees.

provided, however, that these may be extended by us upon payment of additional fees.

MSKCC is entitled to certain success payments if our stock value increases by certain multiples.

The potential payments are based on multiples of the fair market value of our common stock compared with a split-adjusted initial share price of $5.1914 per share, as subject to future adjustments for stock splits, during a specified time period described below.

Our common stock price will be determined by reference to the 45-day volume weighted-average trading price of our common stock.

The potential payments are based on multiples of the fair value of our common stock compared with a split-adjusted initial stock price of $5.1914 per share, as subject to future adjustments for stock splits, during a specified time period described below.

Our common stock price will be determined by reference to the 45-trading day volume weighted-average trading price of our common stock immediately preceding the date of determination.

At our option, payments may be made in cash or common stock.

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Our anti-BCMA CB-011 product candidate contains this BCMA scFv.

Under the terms of the ProMab Agreement, in the event we, or our affiliates or licensees, receive regulatory approval for CB-011, we will owe ProMab low-single-digit percent royalties on net sales by us, our affiliates, and licensees until the expiration, abandonment, or invalidation of the last patent within the assigned patent family (i.e., 2040 for U.S.

Under the terms of the ProMab Agreement, in the event that CB-011 is approved by the FDA, we will owe ProMab low-single-digit percent royalties on net sales until the expiration, abandonment, or invalidation of the last patent within the assigned patent family (i.e., 2040 for U.S.

patents, without patent term adjustment (“PTA”) or patent term extension (“PTE”)).

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If ProMab terminates the ProMab Agreement due to our uncured material breach or bankruptcy, we must cease the manufacture, use, and sale of any products or product candidates incorporating the purchased anti-BCMA scFv.

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Pioneer Hi-Bred International, Inc.

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As consideration for the assignment, we made an upfront payment of $0.5 million and are obligated to pay all patent prosecution and maintenance costs going forward;

up to $2.8 million in regulatory milestones for therapeutic products developed by us, our affiliates, and licensees;

up to $20.0 million in sales milestones over a total of four therapeutics products sold by us, our affiliates, and licensees;

and a percentage of sublicensing revenues received by us for licensing the chRDNA patent family.

up to $2.8 million in regulatory milestones for therapeutic products, up to $20.0 million in sales milestones over a total of four therapeutics products, and a percentage of sublicensing revenues received by us for licensing the chRDNA patent family.

The sublicensing agreements that we entered into prior to December 18, 2020 (for example, the Intellia Agreement discussed below) are not subject to these economics.

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An interim award from the arbitration panel in 2019 determined that both patent families are included in the Intellia Agreement, but the panel granted us an exclusive leaseback to Cas9 chRDNA guides under economic terms to be negotiated by the parties.

On June 16, 2021, we entered into a leaseback agreement with Intellia (“Leaseback Agreement”), which resolved the arbitration proceeding.

Pursuant to the Leaseback Agreement, in exchange for Intellia’s grant to us of an exclusive license to certain intellectual property relating to CRISPR-Cas9, including Cas9 chRDNAs, for use solely in the manufacture of our CB-010 product candidate, we paid Intellia an upfront cash payment of $1.0 million and will pay up to $23.0 million in potential future regulatory and sales milestones.

Additionally, we will owe Intellia low- to mid- single-digit percent royalties on net sales of our CB-010 product candidate by us, our affiliates, and sublicensees until the expiration, abandonment, or invalidation of the last patent within the intellectual property relating to CRISPR-Cas9, including that relating to Cas9 chRDNAs (i.e., 2036, without PTA or PTE).

On June 16, 2021, we entered into a leaseback agreement with Intellia (“Leaseback Agreement”), which resolved the arbitration

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Pursuant to the Leaseback Agreement, in exchange for Intellia’s grant to us of an exclusive license to certain intellectual property relating to CRISPR-Cas9, including Cas9 chRDNAs, for use solely in the manufacture of our CB-010 product candidate, we paid Intellia an upfront cash payment of $1.0 million and we will owe up to $23.0 million in potential future regulatory and sales milestones.

Additionally, we will owe Intellia low- to mid- single-digit percent royalties on net sales of our CB-010 product candidate until the expiration, abandonment, or invalidation of the last patent within the intellectual property relating to CRISPR-Cas9, including that relating to Cas9 chRDNAs (i.e., 2036, without PTA or PTE).

The Regents of the University of California (“UC”) and the University of Vienna (“Vienna”)

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Prior to such time that we are selling products, we owe UC/Vienna an annual license maintenance fee.

We may owe UC/Vienna up to $3.4 million in certain regulatory and clinical milestone payments in the field of human therapeutics and diagnostics for products developed by us, our affiliates, and sublicensees.

We will owe UC/Vienna up to $3.1 million in potential regulatory and clinical milestone payments in the field of human therapeutics and diagnostics.

Additionally, we pay UC/Vienna a specified percentage of sublicensing revenue we receive including cash and equity under our sublicensing agreements, subject to certain exceptions.

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Patent and Trademark Office (“USPTO”) and at the European Patent Office (“EPO”).

See Risk Factors - “Our ability to continue to receive licensing revenue and to enter into

new licensing arrangements related to the foundational CRISPR-Cas9 intellectual property will be substantially impaired if such intellectual property is limited by administrative patent proceedings or other patent challenges, ” in Item 1A of this Annual Report on Form 10-K.

See Risk Factors - “Our ability to continue to receive licensing revenue and to enter into new licensing arrangements related to the foundational CRISPR-Cas9 intellectual property will be substantially impaired if such intellectual property is limited by administrative patent proceedings or other patent challenges, ” in Item 1A of this Annual Report on Form 10-K.

On December 15, 2016, we entered into a Consent to Assignments, Licensing and Common Ownership and Invention Management Agreement (“IMA”) with UC, Vienna, Dr.

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We also agreed to various provisions that must be included in all future sublicensing agreements, including specific provisions for exclusive sublicenses.

AbbVie Manufacturing Management Unlimited (“AbbVie”)

On February 9, 2021, we entered into a Collaboration and License Agreement with AbbVie (as amended, “AbbVie Agreement”) with AbbVie.

Under the AbbVie Agreement, we received a $30.0 million upfront, non-refundable and non-creditable, cash payment.

On September 26, 2023, we received notice from AbbVie that AbbVie had elected to terminate the AbbVie Agreement.

By mutual agreement with AbbVie, termination of the AbbVie Agreement became effective on October 25, 2023.

Intellectual Property

We strive to protect and enhance the genome editing technologies that we believe are important to our business by seeking patents to cover our platform technologies.

We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

We also rely on trade secrets to protect aspects of our business that are

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not amenable to, or that we do not consider appropriate for, patent protection.

Our success will depend significantly on our ability to obtain and maintain patent and trade secret protection for our technologies, our ability to defend and enforce our intellectual property rights, and our ability to operate without infringing any valid and enforceable intellectual property rights of third parties.

As of March 1, 2024, we own 59 granted U.S.

patents, including nine U.S.

patents covering our Cas9 and Cas12a chRDNA technologies;

309 granted foreign patents;

and 90 pending patent applications throughout the world.

As of March 1, 2025, we owned 63 granted U.S.

patents, 324 granted foreign patents, and 148 pending patent applications throughout the world.

The patent portfolio owned by us includes U.S.

and foreign patents and patent applications covering methods and compositions relating generally to our Cas9 chRDNA and Cas12a chRDNA guides (which, for granted U.S.

and foreign patents and patent applications covering methods and compositions relating generally to our Cas9 chRDNA and Cas12a chRDNA technologies (which, for granted U.S.

patents, without PTA or PTE, will expire in 2036).

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We have exclusively in-licensed intellectual property covering the anti-CLL-1 scFv of our CB-012 product candidate from MSKCC (which, upon grant, without PTA or PTE or other extensions, will expire in 2040).

Additionally, we have extensive patent protection on CRISPR Type I systems, CRISPR-Cas9 methods and compositions, and other genome-editing technologies.

Additionally, we have substantial patent protection on CRISPR Type I systems, CRISPR-Cas9 methods and compositions, and other genome-editing technologies.

The patent term in the United States and other countries is 20 years from the date of filing of the first non-provisional application to which priority is claimed.

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Additionally, under the Drug Price Competition and Patent Term Restoration Act of 1984 (“Hatch-Waxman Amendments”), the term of a patent that covers an FDA-approved biologic may also be eligible for a PTE of up to five years, which is designed to compensate for the patent term lost during clinical trials and the FDA regulatory review process.

A PTE cannot extend the remaining term of a patent

beyond a total of 14 years from the date of product approval and only one patent claiming the drug product, methods of use or methods of manufacturing may be restored.

Moreover, a patent can only be restored once, and thus, if a single patent is applicable to multiple products, it can only be extended based on one product.

Similar provisions are available in Europe and certain other foreign jurisdictions to extend the term of a patent that covers an approved product.

Without any PTE, the earliest expiration dates of our granted U.S.

patents are in 2032 and the latest expiration dates of our granted U.S.

patents are in 2040.

As of March 1, 2024, we own 21 trademark registrations, including 5 U.S.

A PTE cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent claiming the drug product, methods of use, or methods of manufacturing may be restored.

Moreover, a patent can only be restored once and, if a single patent is applicable to multiple products, it can only be extended based on one product.

Similar provisions to extend the term of a patent that covers an approved product are available in Europe and certain other foreign jurisdictions .

Without any PTE, the earliest expiration date of our granted U.S.

patents is in 2032 and the latest expiration date of our granted U.S.

patents is in 2043.

As of March 1, 2025, we owned 25 trademark registrations worldwide, including 7 U.S.

trademark registrations, and 2 pending trademark applications worldwide.

We have registered “CARIBOU,” “CARIBOU BIOSCIENCES,” “SITE-SEQ,” and the Caribou logo as trademarks in relevant classes and jurisdictions in the United States and certain other jurisdictions.

We have registered “CARIBOU,” “CARIBOU BIOSCIENCES,” “SITE-SEQ,” and the Caribou logo as trademarks in relevant classes and jurisdictions in the United States, European Union, and certain other jurisdictions.

Furthermore, we rely upon trade secrets, know-how, continuing technological innovation and potential in-licensing opportunities to develop and maintain our competitive position.

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We also enter into confidentiality and invention assignment agreements with our employees and our agreements with consultants include invention assignment obligations.

We currently compete across the fields of genome editing and cell therapy.

We believe that our novel Cas12a chRDNA genome-editing platform has broad potential applicability across human therapeutic indications, and our strategy is to demonstrate our platform’s capability by first developing improved allogeneic cell therapies in hematologic oncology indications.

The biopharmaceutical industry, and in particular the genome-editing and cell therapy fields, are characterized by intense investment and competition aimed at rapidly advancing new technologies.

Our platform and therapeutic product candidates are expected to face substantial competition from multiple technologies, marketed products, and numerous other therapies being developed by other biopharmaceutical companies, academic research institutions, governmental agencies, and private research institutions.

Many of our competitors have substantially greater financial, technical, and other resources, such as larger research and development staff, established manufacturing capabilities and facilities, and experienced marketing organizations with well-established sales forces.

In addition, there is substantial patent infringement litigation in the biopharmaceutical industry and, in the future, we may bring or defend such litigation against our competitors.

Compared to first-generation genome-editing approaches, our chRDNA platform has shown improved specificity, a reduction in off-target edits and translocations, and an advanced capability to perform multiplexed edits, in particular multiplexed insertions.

Although we believe that our scientific expertise, novel technologies, and intellectual property position offer competitive advantages, we face competition from multiple other genome-editing technologies and companies.

Other companies developing CRISPR-based technologies include, among others, Arbor Biotechnologies, Beam Therapeutics Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Intellia Therapeutics, Inc., MammothBiosciences, Inc., Metagenomi Technologies,Inc., and Scribe Therapeutics, Inc.

Companies developing other genome-editing technologies include, among others,Allogene Therapeutics, Inc., Cellectis S.A., Precision BioSciences, Inc., and Sangamo Therapeutics, Inc.

We believe that our CAR-T cell therapy product candidates have the potential to offer beneficial products to patients due to genome edits we make to improve their activity with the goal of extending robust CAR-T cell antitumor activity in patients.

Due to the promising therapeutic effect of cell therapies, and the potential benefit of allogeneic treatment alternatives, we expect increasing competition from new and existing companies, which include, among others:

We currently compete across the fields of cell therapy and genome editing.

We believe that our novel CRISPR-Cas12a chRDNA genome-editing platform has broad potential applicability across human therapeutic indications, and our strategy is to demonstrate our platform’s capability by first developing improved allogeneic cell therapies in hematologic oncology and autoimmune diseases.

The biopharmaceutical industry, in particular the cell therapy and genome editing fields, is characterized by intense investment and competition aimed at rapidly advancing new technologies.

Our platform and therapeutic product candidates are expected to face substantial competition from multiple technologies, marketed products, and numerous other therapies being developed by other biopharmaceutical companies, larger and better funded pharmaceutical companies, academic research institutions, governmental agencies, and private research institutions.

Many of our competitors, either alone or with their collaborators, have substantially greater financial, technical, and other resources, such as larger research and development staff, and/or greater expertise in research and development, preclinical testing, conducting clinical trials, established manufacturing capabilities and facilities, and experienced marketing organizations with well-established sales forces.

In addition, there is extensive patent infringement litigation in the biopharmaceutical industry and, in the future, we may bring or defend such litigation against our competitors.

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We believe that our CAR-T cell therapy product candidates have the potential to offer beneficial products to patients due to genome edits we make with our chRDNA technology with the goal of extending robust CAR-T cell activity in patients.

Because of the promising therapeutic effect of cell therapies, and the potential benefit of allogeneic treatment alternatives, we expect increasing competition from new and existing companies, which include, among others:

• Autologous T cell therapy :

2seventy bio, Inc., Adaptimmune Therapeutics plc, Arcellx, Inc., Autolus Therapeutics plc, AvenCell Therapeutics, Inc., Bristol-Myers Squibb Company, CARGO Therapeutics, Inc., Gracell Biotechnologies, an AstraZeneca PLC company, Janssen Biotech, Inc., ImmPACT Bio USA, Inc., Kite, a Gilead Company, Legend Biotech Corporation, Lyell Immunopharma, Inc., Novartis International AG, Poseida Therapeutics, Inc., Precigen, Inc., and Vor Biopharma Inc.;

Autologous T cell therapies directed at CD19 have been commercialized by Novartis AG (Kymriah®), Kite Pharma, Inc., a Gilead Sciences, Inc.

company (Yescarta®, Tecartus®), and Bristol-Myers Squibb Company (Breyanzi®) and are witnessing increased adoption in the marketplace.

Autologous cell therapies directed at BCMA have been commercialized by 2seventy bio, Inc.

with their partner, Bristol-Myers Squibb Company, (Abecma®) and Legend Biotech Corporation with their partner, Janssen Biotech, Inc., a Johnson & Johnson company, (Carvykti®).

Both Abecma and Carvykti cell therapies have succeeded in pivotal trials in earlier lines of r/r MM and are expected to gain label extensions into this market.

Autologous T cell therapies are being developed by a number of additional companies, including but not limited to, 2seventy bio, Inc., Adaptimmune Therapeutics PLC, Alaunos Therapeutics, Inc., Arcellx, Inc., Arsenal Biosciences, Inc., Astellas Pharma Inc., Autolus Therapeutics plc, AvenCell Therapeutics, Inc., Bristol-Myers Squibb Company, Cabaletta Bio, Inc., CARGO Therapeutics, Inc., Eureka Therapeutics, Inc., Gracell Biotechnologies Inc., an AstraZeneca PLC company, Iovance Biotherapeutics, Inc., Janssen Biotech, Inc., Kite Pharma, Inc.

(a Gilead Sciences Inc.

company), Kyverna Therapeutics, Inc., Legend Biotech Corporation, Lyell Immunopharma, Inc., March Biosciences, Inc., Miltenyi Biotec, Mustang Bio, Inc., Novartis AG, Precigen, Inc., Regeneron Pharmaceuticals, Inc.

(through its acquisition of the 2seventy bio, Inc.

research pipeline), F.

Hoffman-La Roche Ltd (through its acquisition of Poseida Therapeutics, Inc.), TCR² Therapeutics Inc., Triumvira Immunologics Inc., TScan Therapeutics, Inc., and Vor Biopharma Inc.;

• In vivo T cell therapy :

Myeloid Therapeutics, Inc.

and Umoja Biopharma;

Companies such as Abintus Bio, Inc., Capstan Therapeutics, Inc., GigaMune, Inc., Interius BioTherapeutics, Inc., Kelonia Therapeutics, Inc., Myeloid Therapeutics, Inc., and Umoja Biopharma, Inc.

are developing in vivo T cell therapies;

• Allogeneic T cell therapy:

Allogene Therapeutics, Inc.

Atara Biotherapeutics, Inc., AvenCell Therapuetics, Inc., Cellectis S.A., Celyad Oncology SA, CRISPR Therapeutics AG, Fate Therapeutics, Inc., Gracell

Biotechnologies, an AstraZeneca PLC company, Imugene Limited, Kite, a Gilead Company, Legend Biotech Corporation, Poseida Therapeutics, Inc., Sana Biotechnology, Inc., and Vor Biopharma Inc.;

• Allogeneic NK therapy:

Artiva Biotherapeutics, Inc., Celularity Inc., Century Therapeutics, Inc., Fate Therapeutics, Inc., ImmunityBio, Inc., Nkarta, Inc., NKGen Biotech, Inc., Oncternal Therapeutics, Inc., and Takeda Pharmaceutical Company Limited;

Other companies are developing allogeneic T-cell therapies, including Allogene Therapeutics, Inc., Atara Biotherapeutics, Inc., AvenCell Therapuetics, Inc., Cellectis S.A., Celyad Oncology SA, CRISPR Therapeutics AG, Fate Therapeutics, Inc., Gracell Biotechnologies (an AstraZeneca PLC company), Imugene Limited, Kite Pharma, Inc.

(a Gilead Sciences, Inc.

company), Legend Biotech Corporation, March Biosciences, Inc., F.

Hoffman La-Roche Ltd (through its acquisition of Poseida Therapeutics, Inc.), Sana Biotechnology, Inc., and Vor Biopharma Inc.;

• Allogeneic NK cell therapy:

Companies are developing allogeneic NK cell therapies, including Artiva Biotherapeutics, Inc., Celularity Inc., Century Therapeutics, Inc., Fate Therapeutics, Inc., ImmunityBio, Inc., Nkarta, Inc., NKGen Biotech, Inc., Oncternal Therapeutics, Inc., Senti Biosciences, Inc., and Takeda Pharmaceutical Company Limited;

• Other cell therapies:

Other companies are developing CAR-expressing immune cell therapies derived from macrophages, including Carisma Therapeutics Inc.;

from regulatory T cells, including Kyverna Therapeutics;

and from gamma-delta T cells, including Adicet Bio, Inc., Cytomed Therapeutics Limited, and Takeda Pharmaceutical Company Limited;

from regulatory T cells, including Kyverna Therapeutics, Inc.;

and from gamma-delta T cells, including Adicet Bio, Inc., CytoMed Therapeutics Limited, IN8bio, Inc., TC BioPharm (Holdings) PLC, and Takeda Pharmaceutical Company Limited;

• Other oncology therapeutics:

Multiple biotechnology and pharmaceutical companies developing other directly competitive technologies, such as small molecule, antibody, bi-specific antibody, and antibody-drug conjugates;

Multiple biotechnology and pharmaceutical companies are developing other directly competitive technologies, such as small molecule, antibody, bi-specific antibody, and antibody-drug conjugates;

• Non-oncology therapeutics :

Several companies are also exploring the use of CAR-T cell therapies for the treatment of autoimmune disorders, often including against the same targets as in the oncology field (e.g., CD19, BCMA).

Such autoimmune disorders include lupus nephritis, systemic lupus erythematosus, pemphigus vulgaris, myasthenia gravis, and multiple sclerosis.

These companies include Fate Therapeutics, Inc., Kite, a Gilead company, Kyverna Therapeutics, Luminary Therapeutics, Nkarta, Inc., and Sana Biotechnology, Inc.

Several companies are also exploring the use of CAR-T cell therapies for the treatment of autoimmune diseases, often including against the same targets as in the oncology field (e.g., CD19, BCMA).

Such autoimmune diseases include LN, SLE, pemphigus vulgaris, myasthenia gravis, and multiple sclerosis.

These companies include BRL Medicine Inc., Fate Therapeutics, Inc., Kite Pharma, Inc.

(a Gilead Sciences, Inc.

company) Kyverna Therapeutics, Inc., Luminary Therapeutics, Inc., Nkarta, Inc., and Sana Biotechnology, Inc.

in allogeneic cell therapies;

and Atara Biotherapeutics, Inc., Autolus Therapeutics plc, Bristol-Myers Squibb Company, Cabaletta Bio, Inc., Cartesian Therapeutics, Inc., Century Therapeutics, Kyverna Therapeutics, Lyell Immunopharma, Inc., and Novartis AG in autologous cell therapies.

For a discussion of the risks related to competition, see Risk Factors - “We face significant competition from other biotechnology and pharmaceutical companies, which may result in other companies developing or commercializing products before, or more successfully than, we do, thus rendering our product candidates non-competitive or reducing the size of the market for our product candidates.

Our operating results will suffer if we fail to compete effectively,” in Item 1A of this Annual Report on Form 10-K .

and Atara Biotherapeutics, Inc., Autolus Therapeutics plc, Bristol-Myers Squibb Company, Cabaletta Bio, Inc., Cartesian Therapeutics, Inc., Century Therapeutics, Inc., iCell Gene Therapeutics Inc., JW (Cayman) Therapeutics Co.

Ltd, Kyverna Therapeutics, Inc., Lyell Immunopharma, Inc., and Novartis AG in autologous cell therapies.

We also face competition from non-cell-based treatments offered by companies such as Amgen Inc., AstraZeneca PLC, Bristol-Myers Squibb Company, F.

Hoffman-La Roche Ltd, GlaxoSmithKline Capital plc, Merck & Co., Inc., and Pfizer Inc.

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Compared to first-generation genome-editing approaches, our chRDNA platform has shown improved specificity, a reduction in off-target edits and translocations and, when paired with Cas12a, an advanced capability to perform multiplexed edits, in particular multiplexed insertions.

Other companies developing CRISPR-based technologies include, among others, Arbor Biotechnologies, Inc., Beam Therapeutics Inc., CRISPR Therapeutics AG, Editas Medicine, Inc., Intellia Therapeutics, Inc., Mammoth Biosciences, Inc., Metagenomi, Inc., and Scribe Therapeutics, Inc.

Companies developing other genome-editing technologies include, among others, Allogene Therapeutics, Inc., Cellectis S.A., Precision BioSciences, Inc., Prime Medicine, Inc., Sangamo Therapeutics, Inc., and Wave Life Sciences Ltd.

Manufacturing

Manufacturing of both autologous and allogeneic cell therapies requires multiple components and is complex, and there are many similarities in the processes for both kinds of therapies.

The advantage of allogeneic therapies is the use of cells from healthy donors and therefore the ability to prepare, qualify, and release clinical material in advance of patient need.

For our CAR-T product candidates, we have optimized the manufacturing process that we developed in-house and have transferred the manufacturing to a CMO that manufactures cGMP-grade material for our clinical trials.

Additionally, we have developed different analytical methods to understand the integrity of our cells based upon our manufacturing process.

Manufacturing CAR-T cell therapies requires multiple components.

Allogeneic CAR-T cell therapies are manufactured with cells from healthy donors and clinical product candidates are prepared, qualified, and released in advance.

After manufacture, allogeneic CAR-T therapies are cryogenically stored in freezers and are readily available for patient treatment.

To date, we have successfully scaled our manufacturing processes so that one manufacturing run from a healthy donor can produce sufficient cell yield for approximately 150 doses of CB-010.This is in contrast to commercially available autologous CAR-T cell therapy where one manufacturing run is required for each patient to be treated using the patient’s cells that may have already been depleted by prior treatments and this process can take several weeks to months to deliver product for patient treatment.

For our CAR-T product candidates, we have optimized the manufacturing process that we developed in-house and have transferred the manufacturing to CMOs that manufacture current good manufacturing practices (“cGMP”)-grade material for our clinical trials.

Additionally, we have developed different analytical methods to understand the integrity and potency of our cells based upon our manufacturing process.

We have made a significant investment in process development to control our product candidate characteristics and to also improve our supply chain capabilities.

Figure 25 below describes the process we have developed for the manufacturing of CB-010 CAR-T cells.

We use electroporation for the genome-editing step in our process.

We use an instrument licensed from Maxcyte, Inc.

to achieve high levels of genome editing at manufacturing scale.

Our process includes an important step prior to cryopreservation that

significantly removes residual TCR-expressing cells to reduce the likelihood that CB-010 cells will induce GvHD in patients.

Our internal process development team developed the manufacturing process for CB-010 and transferred it to a CMO.

Figure 26 below describes the process we have developed for the manufacturing of CB-011 CAR-T cells, which also includes the residual TCR removal step.

Our internal process development team developed the manufacturing process for CB-011 and transferred it to a CMO.

Figure 27 below describes the process we have developed for the manufacturing of CB-012 CAR-T cells, which also includes the residual TCR removal step.

Our internal process development team developed the manufacturing process for CB-012 and transferred it to a CMO.

For the manufacturing of our allogeneic CAR-T cell therapy product candidates, we have developed a platform process that is scaled to eventually support commercially manufacturing.

Our process development and manufacturing core competencies and advantages include:

• a platform process that allows optimization and learnings across all of our product candidates and preclinical research programs;

• internal process development to facilitate technical transfer to manufacturing sites;

• readily available and established equipment that further enables the transfer from process development lab to cGMP operations;

• optimization and learnings across all of our product candidates and preclinical research programs, allowing for consistency and increased process robustness;

• internal process development to facilitate optimization of manufacturing processes and technical transfers to manufacturing sites;

• readily available and established equipment that further enables the transfer from our process development lab to cGMP operations;

• custom engineering and development to create the necessary specific requirements for our product candidates, while leveraging the broader platform to ensure robust processes;

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• process understanding and cell manufacturing control for continuous optimization of productivity and product candidate quality;

• closed manufacturing system;

• closed manufacturing systems;

• highly specific development efforts focused on enhancing cell viability;

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• process control and optimization, allowing for increased retention of early memory T cell phenotypes;

• platform scale and efficiency to accommodate high dose yield per batch, with optimization for further commercial supply process.

The CMO that is manufacturing the phase 1 clinical supply of our CB-010, CB-011, and CB-012 product candidates is located in the United States and is subject to cGMP requirements.

We have a dedicated cGMP suite for the manufacture of our products.

We use multiple CMOs to individually manufacture the starting materials for our product candidates, including cGMP chRDNA guides, Cas9 and Cas12a proteins, and AAV6 vectors used in the manufacture of our CAR-T cells.

We expect to rely on our CMOs for the manufacturing of our product candidates to expedite readiness for future clinical trials, and most of these CMOs have capabilities for commercial manufacturing.

• platform scale and efficiency to accommodate high dose yield per batch, with optimization for further commercial supply processes.

The contract manufacturing organizations (“CMOs”) that are manufacturing the phase 1 clinical supplies of our product candidates are located in the United States and are subject to cGMP requirements.

We have dedicated cGMP suites

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at our CMOs for the manufacture of our cell therapy product candidates.

We use multiple CMOs to individually manufacture the critical and starting materials for our product candidates, including cGMP chRDNA guides, Cas9 and Cas12a proteins, and AAV6 vectors used in the manufacture of our CAR-T cells.

Our chRDNA genome-editing is a next-generation CRISPR technology that does not rely on lentiviral or retroviral genome-editing methods, which are used in commercially available autologous CAR-T cell therapies to insert the CAR gene randomly into the genome, which may increase the risk of genomic mutagenesis.

We expect to rely on our CMOs for manufacturing our product candidates to expedite readiness for future clinical trials, and most of these CMOs have demonstrated capabilities for commercial manufacturing.

Additionally, we may decide to build our own manufacturing facility in the future, or we may deploy a hybrid approach to manufacturing, to provide us with greater flexibility and control over our clinical or commercial manufacturing needs.

Government Regulation

As a biotechnology company, we are subject to extensive legal and regulatory requirements.

For example, we may need approval from regulatory agencies for our research, development, testing, manufacture, quality control, packaging, storage, record keeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of our product candidates.

As a biotechnology company, we are subject to extensive legal and regulatory requirements, including those related to research, development, testing, manufacture, product approval and licensure, quality control, packaging, storage, record keeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of our product candidates.

Relevant regulatory authorities include, but are not limited to, the FDA;

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As we seek approval to market and distribute a new biologic in the United States, we generally must satisfactorily complete each of the following steps:

• preclinical laboratory tests and formulation studies performed in accordance with the FDA’s current Good Laboratory Practice (“cGLP”) regulations;

• nonclinical studies performed in accordance with the FDA’s current Good Laboratory Practice (“cGLP”) regulations;

• manufacture and testing of clinical investigational product according to cGMPs;

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• performance of adequate and well-controlled human clinical trials required to establish the safety and efficacy of the product candidate for each proposed indication, in accordance with the FDA’s current Good Clinical Practice (“cGCP”) regulations including, but not limited to, informed consent and investigator disclosure requirements;

• preparation and submission to the FDA of a BLA for marketing approval of our product candidates for one or more proposed indications, including submission of detailed information on the manufacture and composition of our product candidates and proposed labeling;

• preparation and submission to the FDA of a BLA seeking approval of our product candidates for one or more proposed indications, including submission of detailed information on the manufacture and composition of our product candidates and proposed labeling;

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• review of the BLA by an FDA advisory committee, where applicable;

• satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities, including those of any third-party manufacturers, at which the product, or components thereof, are produced in order to assess compliance with cGMP requirements and to ensure that the facilities, methods, and controls are adequate to preserve and ensure the product’s identity, strength, quality, and purity, and, if applicable, the FDA’s current Good Tissue Practice (“cGTP”), for the use of human cell and tissue products;

• satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities, including those of any third-party manufacturers, at which the product, or components thereof, are produced in order to assess compliance with cGMP requirements and to ensure that the facilities, methods, and controls are adequate to preserve and ensure the product’s safety, purity, and potency, and, if applicable, the FDA’s current Good Tissue Practice (“cGTP”), for the use of human cell and tissue products;

• satisfactory completion of any FDA audits of the nonclinical study and clinical trial sites to ensure compliance with cGLPs and cGCPs, respectively, and the integrity of nonclinical and clinical data in support of the BLA;

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• compliance with any post-approval requirements, including the potential requirement to implement Risk Evaluation and Mitigation Strategy (“REMS”), adverse event reporting, and compliance with any post-approval studies required or requested by the FDA.

Preclinical Studies and Investigational New Drug Applications

Before testing any investigational biologic product candidate in humans, our product candidates must undergo preclinical testing.

Preclinical tests include laboratory evaluations of product chemistry, formulation, and stability.

The FDA Modernization Act 2.0, which was enacted in December 2022, removed the historical requirements that animal testing results be submitted to the FDA for the agency’s review before a human clinical trial may begin.

The conduct of the preclinical tests and the formulation of the compounds for use in the preclinical testing must comply with federal regulations and/or requirements.

The results of the preclinical tests, together with manufacturing information and analytical data, are submitted to the FDA as part of an IND application.

Nonclinical Studies and Investigational New Drug Applications

Before testing any investigational biologic product candidate in humans, we must submit an IND application and receive clearance from the FDA to initiate a clinical trial.

The results of our nonclinical testing, including laboratory evaluation of product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy of the product, together with manufacturing information, are submitted to the FDA as part of the IND application.

An IND is an exemption from the restrictions of the FDCA, which would otherwise preclude an unapproved biologic product candidate from being shipped in interstate commerce.

Under a cleared IND, the unapproved biologic product candidate may be shipped in interstate commerce for use in an investigational clinical trial, provided that the product candidate meets certain quality and labeling requirements.

The FDA has 30 calendar days after receipt of our IND application to review and decide whether we may proceed to human clinical trials.

During or after its review, the FDA may raise concerns or questions about our product candidate or conduct of the proposed clinical trial, including concerns that human research subjects could be exposed to unreasonable and significant health risks.

If the FDA raises concerns or questions during this 30-day period, including safety concerns or concerns due to regulatory non-compliance, we and the FDA must resolve any outstanding concerns before the clinical trials can begin.

In certain cases, the FDA may impose a partial or complete clinical hold with respect to our product.

Such a clinical hold would delay either a proposed clinical trial, or cause suspension of an ongoing clinical trial, until all outstanding concerns

have been adequately addressed, and the FDA has notified us that our clinical trials may proceed or recommence.

An IND automatically becomes effective 30 calendar days after receipt by the FDA, unless before that time the FDA places the trial on clinical hold.

In such a case, the IND sponsor must correct the deficiencies cited in the hold letter or otherwise satisfy the FDA that the investigation may proceed before the clinical trial can begin.

When the sponsor submits a response to the issues identified in the hold letter, the FDA must respond in writing to the sponsor within 30 days of the complete response by either removing or maintaining the clinical hold.

The FDA may impose a partial or full clinical hold with respect to our product candidate.

In certain cases, we may not be able to proceed at all with our proposed clinical trial.

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Clinical trials are conducted under study protocols detailing, among other things, the objectives of the clinical trial, inclusion, and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

A protocol for each clinical trial and subsequent protocol amendments must be submitted to the FDA as part of the IND and must also be reviewed by an IRB.

A protocol for each clinical trial and subsequent protocol amendments must be submitted to the FDA as part of the IND.

If we wish to conduct a clinical trial outside of the United States, we may, but need not, obtain FDA authorization to conduct the clinical trial under an IND application.

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clinical trial is not conducted under an FDA IND application, we may submit data from a well-designed and well-conducted clinical trial to the FDA in support of our BLA as long as the clinical trial is conducted in compliance with cGCP and the FDA is able to accept the data from the clinical trial and/or through an onsite inspection if the FDA deems it necessary.

In certain cases, however, the FDA may refuse to approve drugs based only on clinical trials conducted outside of the United States.

For example, an FDA panel previously recommended against approving an immunotherapy drug that was tested only in China, citing potential concerns about the diversity of the clinical trial population, among others.

A senior FDA official has also voiced concerns previously about approving drugs that are developed and tested only in overseas markets.

It is not clear how or whether FDA’s policies may change in the future.

For clinical trials conducted in the United States, each clinical trial must be reviewed and approved by an IRB, either centrally or individually at each institution at which our clinical trials will be conducted.

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This group receives and reviews data from the clinical trial on an ongoing basis and may recommend continuation of the clinical trial as planned, changes in clinical trial conduct, or cessation of the clinical trial at designated check points based on such data.

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In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules may be subject to oversight of institutional biosafety committees (“IBCs”), as set forth in the National Institutes of Health (“NIH”) Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (“NIH Guidelines”).

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Although the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

Furthermore, the Food and Drug Omnibus Reform Act of 2022 requires clinical trial sponsors to submit a diversity action plan for clinical trials, unless a waiver is granted by the FDA for reasons such as prevalence of the disease or condition, impracticality of implementing such a diversity action plan, or if such implementation would be against the interest of public health during a public health emergency.

Unless the FDA has granted a waiver, sponsors must submit such action plans by the time the sponsors submit study protocols for its phase 3 clinical trial or other pivotal clinical trial.

Furthermore, the Food and Drug Omnibus Reform Act of 2022 (“FDORA”) requires a clinical trial sponsor to submit a diversity action plan for clinical trials, unless a waiver is granted by the FDA for reasons such as prevalence of the disease or condition, impracticality of implementing such a diversity action plan, or if such implementation would be against the interest of public health during a public health emergency.

Unless the FDA has granted a waiver, a sponsor must submit such action plan by the time the sponsor submits a protocol for a phase 3 clinical trial or other pivotal clinical trial.

The action plan must include information such as the sponsor’s goal for enrollment (by sex, ethnic characteristics, age), the rationale behind the enrollment goals, the subject patient population, potential barriers for enrollment, among others.

requirement will become applicable to all clinical trials that begin enrollment 180 days after FDA publishes its final guidance on this topic.

This requirement is not yet in effect as it will become applicable to all clinical trials that begin enrollment 180 days after FDA publishes its final guidance on this topic.

In January 2025, the FDA removed its June 2024 guidance on clinical trial diversity action plans from its website, and it is not clear how the FDA will enforce the statutory requirement under FDORA.

Clinical trials typically are conducted in three sequential phases.

however, the phases may overlap or may be combined.

• Phase 1 clinical trials are initially conducted in a limited population of healthy humans or, for our product candidates, in patients, such as cancer patients, in order to test the product candidate for safety, including adverse effects, dose tolerance, absorption, metabolism, distribution, excretion, and pharmacodynamics, and to identify a recommended phase 2 dose.

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We may conduct multiple phase 2 clinical trials to obtain information prior to beginning larger and costlier phase 3 clinical trials.

The phase 2 clinical trial for our product candidates may serve as the pivotal phase 3 trial, in which case a separate phase 3 clinical trial will not be necessary.

• Phase 3 clinical trials are undertaken within an expanded patient population to further evaluate dosage and gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling.

In appropriate circumstances, a phase 2 clinical trial may serve as the basis for an application, in which case a separate phase 3 clinical trial will not be necessary.

• Phase 3 clinical trials are undertaken within an expanded patient population to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling.

These phases may overlap or be combined.

For example, a phase 1/2 clinical trial may contain both a dose-escalation stage and a dose-expansion stage, the latter of which may confirm tolerability at the recommended dose for expansion in future clinical trials (as in traditional phase 1 clinical trials) and provide insight into the anti-tumor effects of the investigational therapy in selected subpopulation(s).

Typically, during the development of oncology therapies, all subjects enrolled in phase 1 clinical trials are disease-affected patients and, as a result, considerably more information on clinical activity may be collected during such trials than during Phase 1 clinical trials for non-oncology therapies.

In most cases, the FDA requires two adequate and well-controlled phase 3 clinical trials to demonstrate the safety and efficacy of the biologic.

In rare instances, a single phase 3 trial may be sufficient when either (i) the trial is a large, multicenter trial demonstrating internal consistency and a statistically very persuasive finding of a clinically meaningful effect on mortality, irreversible morbidity or prevention of a disease with a potentially serious outcome and confirmation of the result in a second trial would be practically or ethically impossible, or (ii) the single trial is supported by confirmatory evidence.

Approval on the basis of a single trial may be subject to a requirement for additional post-approval studies.

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In addition, the manufacturer of an investigational biologic in a phase 2 or phase 3 clinical trial for a serious or life-threatening disease is required to make available, such as by posting on its website, its policy on evaluating and responding to requests for expanded access to such investigational drug or biologic.

During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and clinical trial investigators.

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Other external events may occur that can affect the conduct of our clinical trials, such as pandemics or government shutdowns.

In some cases, the FDA may approve a BLA for our product candidate but require us to conduct additional clinical trials to further assess the product candidate’s safety and effectiveness after approval.

Such post-approval trials are typically referred to as phase 4 clinical trials or post-approval commitments.

These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication and to document a clinical benefit in the case of biologics approved under accelerated approval regulations.

Failure to exhibit due diligence in conducting phase 4 clinical trials or post-approval commitments could result in withdrawal of approval for our products.

Guidance Governing Gene Therapy Products

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Within the FDA, the Center for Biologics Evaluation and Research (“CBER”) regulates gene therapy products.

Within CBER, the review of gene therapy and related products is consolidated in the Office of Tissues and Advanced Therapies, and the FDA has established the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its reviews.

Within CBER, the review of gene therapy and related products is consolidated in the Office of Therapeutic Products, and the FDA has established the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its reviews.

The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols.

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Guidance for Industry,” which provides recommendations regarding collection and handling of cellular starting materials, vector manufacturing and testing processes, CAR-T cell design and development considerations, pharmacology and toxicology, clinical trial considerations, manufacturing processes, analytical comparability, etc.

cytokine-release syndrome and neurological toxicities, diagnostic tests that can identify patients with tumors that have the target antigens, selection of appropriate dosage levels based on viable transduced CAR-T cells, etc.

In this guidance the FDA outlined factors that sponsors should consider in conducting clinical trials using CAR-Ts, including defining appropriate study populations based on potential toxicities of CAR-T cells, such as cytokine-release syndrome and neurological toxicities, diagnostic tests that can identify patients with tumors that have the target antigens, selection of appropriate dosage levels based on viable transduced CAR-T cells, etc.

The FDA also issued a guidance document titled “Human Gene Therapy Products Incorporating Human Genome Editing” in January 2024, which provides recommendations for sponsors that are developing gene therapy products involving genetic editing of somatic cells, as well as information that sponsors should provide to the FDA prior to beginning a clinical trial, including information on the design of the gene editing component;

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The FDA also has issued other guidance documents that relate to gene therapies, such as “Human Gene Therapy for Rare Diseases,” and it is likely that the FDA will continue to issue additional guidelines in the future that may affect our product candidates.

Although the FDA has indicated that its guidance documents regarding gene therapies are not legally binding, we believe that our compliance with them is likely necessary to gain approval for any product candidate we may develop.

Although guidance documents are not legally binding, we believe that following FDA’s recommendations set forth in them is likely necessary to gain approval for any product candidate we may develop.

The guidance documents provide additional factors that the FDA will consider at each of the above stages of development and relate to, among other things, the proper preclinical assessment of gene therapies;

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Depending on the product type, long term follow up can be up to 15 years or as short as five years.

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Clinical Trial Registry

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Review and Approval of a BLA

The results of product candidate development, preclinical testing, and clinical trials, including negative or ambiguous results as well as positive findings, are submitted to the FDA as part of a BLA requesting a license to market the product.

The BLA must contain sufficient manufacturing information and detailed information on the composition of the product candidate and proposed labeling as well as payment of a user fee.

The results of product candidate development, nonclinical testing, and clinical trials, including negative or ambiguous results as well as positive findings, are submitted to the FDA as part of a BLA requesting a license to market the product.

The BLA must contain sufficient manufacturing information and detailed information on the composition of the product candidate and proposed labeling as well as payment of a user fee, unless the criteria for a waiver or exemption are met.

Under the PHSA, the FDA will approve a BLA if it determines that our product candidate is safe, pure, and potent and the manufacturing facility meets standards designed to ensure that our product continues to be safe, pure, and potent.

The FDA has 60 calendar days after submission of a BLA to conduct an initial review to determine whether the BLA is acceptable for filing based on the agency’s threshold determination that the BLA is sufficiently complete to permit substantive review.

Once the submission has been accepted for filing, the FDA begins an in-depth review of the application.

Under the goals and policies agreed to by the FDA under the Prescription Drug User Fee Act (“PDUFA”), the

FDA has 10 months in which to complete its initial review of a standard application and respond to us, and six months for a priority review of the application.

Once the submission has been filed, the FDA begins an in-depth review of the application.

Under the goals agreed to by the FDA under the Prescription Drug User Fee Act (“PDUFA”), for a new molecular entity, the FDA has 10 months from date that the FDA filed the BLA in which to complete its initial review of a standard application and respond to us, and six months from such filing date for a priority review of the application.

The FDA does not always meet its PDUFA goal dates for standard and priority BLAs.

The review process may often be significantly extended by FDA requests for additional information or clarification.

The review process and the PDUFA goal date may be extended by three months if the FDA requests, or if we otherwise provide through the submission of a major amendment, additional information or clarification regarding information already provided in the submission within the last three months before the PDUFA goal date.

Under the PHSA, the FDA may approve a BLA if it determines that our product candidate is safe, pure, and potent and the manufacturing facility meets standards designed to ensure that our product continues to be safe, pure, and potent.

On the basis of the FDA’s evaluation of the application and accompanying information, including the results of the inspection of the manufacturing facilities and any FDA audits of nonclinical study and clinical trial sites to ensure compliance with cGMPs and cGCPs, respectively, the FDA may issue an approval letter or a complete response letter.

The review process and the PDUFA goal date may be extended by three months if the FDA determines that we have submitted a major amendment.

The FDA may refer our BLA to an advisory committee for review, evaluation, and recommendation as to whether our BLA should be approved.

In particular, the FDA may refer to an advisory committee application for biologic products that present difficult questions of safety or efficacy.

Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates, and provides a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

On the basis of the FDA’s evaluation of the application and accompanying information, including the results of the inspection of the manufacturing facilities and any FDA audits of nonclinical study and clinical trial sites to ensure compliance with cGMPs and cGCPs, respectively, the FDA will issue an approval letter or a complete response letter.

An approval letter authorizes commercial marketing of our product candidate with specific prescribing information for specific indications.

If our BLA is not approved, the FDA will issue a complete response letter, which will contain the conditions that must be met in order to secure final approval of the application and, when possible, will outline recommended actions we might take to obtain approval of our BLA.

If our BLA is not approved, the FDA will issue a complete response letter, which will contain the deficiencies that preclude approval of the application and outline recommended actions we might take to obtain approval of our BLA.

If we receive a complete response letter, we may submit to the FDA information that represents a complete response to the issues identified by the FDA.

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The classification of a resubmission is based on the information submitted by us in response to the complete response letter.

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Under the goals and policies agreed to by the FDA under the PDUFA, the FDA has two months to review a class 1 resubmission and six months to review a class 2 resubmission.

The FDA will not approve an application until issues identified in the complete response letter have been addressed.

The FDA will not approve an application until deficiencies identified in the complete response letter have been addressed.

Alternatively, if we receive a complete response letter, we may either withdraw our BLA or request a hearing.

The FDA may also refer our BLA to an advisory committee for review, evaluation, and recommendation as to whether our BLA should be approved.

In particular, the FDA may refer to an advisory committee application for biologic products that present difficult questions of safety or efficacy.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

If the FDA approves any one of our products, it may limit the approved indications for use of our products.

The FDA may also require that contraindications, warnings, or precautions be included in the product labeling.

In addition, the FDA may call for post-approval studies, including phase 4 clinical trials, to further assess a product’s safety after approval.

In addition, the FDA may call for post-approval studies, including phase 4 clinical trials.

The FDA may also require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, to help ensure that the benefits of the product outweigh the potential risks.

REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use (“ETASU”).

ETASU can include, but is not limited to, specific or special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries.

ETASU can include, but are not limited to, specific or special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries.

The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.

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Fast Track, Breakthrough Therapy, Priority Review, and Regenerative Medicine Advanced Therapy Designations

The FDA is authorized to designate certain products for expedited review if such products are intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition.

The FDA is authorized to facilitate and expedite development and review of new drugs intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition.

These programs include fast track designation, breakthrough therapy designation, priority review, and regenerative medicine advanced therapy designation.

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Although these programs are intended to expedite product development and approval, they do not alter the standards for FDA approval.

The FDA may designate one or more of our product candidates for fast track review if our product candidate is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life-threatening disease or condition, and it can be demonstrated that our product candidate has the potential to address unmet medical needs for such a disease or condition.

Our CB-010 and CB-011 product candidates have been designated for fast track review, and, for fast track product candidates, we may have greater interactions with the FDA, and the FDA may

initiate review of sections of our fast track product candidate’s application before the application is complete.

The FDA may designate one or more of our product candidates as a fast track product if our product candidate is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life-threatening disease or condition, and it can be demonstrated that our product candidate has the potential to address an unmet medical need for such a disease or condition.

Our current product candidates have been designated as fast track products, which means we may have greater interactions with the FDA, and the FDA may initiate review of sections of our fast track product candidate’s application before the application is complete.

This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by us, that a fast track product candidate may be effective.

We must also provide, and the FDA must approve, a schedule for the submission of the remaining information, and we must pay applicable application user fees.

However, the FDA’s time period goal for reviewing a fast track application does not begin until the last section of the application is submitted.

However, the FDA’s goal for reviewing a rolling submission does not begin until the last section of the application is submitted.

In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process, or if our designated product candidate development program is no longer being pursued.

Our product candidates may obtain breakthrough therapy designations if they are intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that our product candidates may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The FDA may take certain actions with respect to product candidates with such designations, including holding meetings with us throughout the development process, providing timely advice to us regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team, and taking other steps to design the clinical trials in an efficient manner.

Breakthrough designation may be rescinded if our product candidate no longer meets the qualifying criteria.

The FDA may designate one of more of our product candidates for priority review if our product candidate treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness of the treatment, prevention, or diagnosis of such condition.

Our product candidates may obtain breakthrough therapy designations if they are intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that our product candidates may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

Breakthrough therapy designation may be rescinded if our product candidate no longer meets the qualifying criteria.

The FDA may determine that an application will receive priority review designation if the application is for a product candidate that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.

The FDA makes such determination on a case-by-case basis, compared with other available therapies.

Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting adverse reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation.

A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for acting on a marketing application from 10 months to six months.

The FDA may grant product candidates RMAT designations if such product candidates are regenerative medicine therapies intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that they have the potential to address unmet medical needs for such disease or condition.

A priority review designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for acting on a marketing application from 10 months to six months.

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The FDA may grant product candidate RMAT designations if such product candidates are regenerative medicine therapies intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that they have the potential to address unmet medical needs for such disease or condition.

RMAT designation provides potential benefits that include early interactions and more frequent meetings with the FDA to discuss the development plan for the product candidate and eligibility for rolling review and priority review.

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Regenerative medicine advanced therapy designation may be rescinded if our product candidate no longer meets the qualifying criteria.

The FDA granted CB-010 RMAT designation for r/r LBCL.

Accelerated Approval Pathway

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Product candidates granted accelerated approval must meet the same statutory standards for safety and efficacy as those granted traditional approval.

For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit but is not itself a measure of

clinical benefit.

Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.

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Thus, accelerated approval has been used extensively in the development and approval of products for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit.

The accelerated approval pathway is usually contingent on our agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe our product candidate’s clinical benefit, and, in most cases, the FDA may require that the trial be designed, initiated, and/or fully enrolled prior to approval.

As a result, a product candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of post-approval clinical trials to confirm the effect on the clinical endpoint.

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All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA unless the FDA informs us otherwise.

FDORA included provisions related to the accelerated approval pathway.

Pursuant to FDORA, the FDA is authorized to require a post-approval study to be underway prior to approval or within a specified time period following approval.

FDORA also requires the FDA to specify conditions of any required post-approval study, which may include milestones such as a target date of study completion and requires sponsors to submit progress reports for required post-approval studies and any conditions required by the FDA not later than 180 calendar days following approval and not less frequently than every 180 days thereafter until completion or termination of the study.

FDORA enables the FDA to initiate enforcement action for the failure to conduct with due diligence a required post-approval study, including a failure to meet any required conditions specified by the FDA or to submit timely reports.

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Post-Approval Regulation

If regulatory approval for marketing of any of our product candidates is obtained, we will be required to comply with all regular post-approval regulatory requirements as well as any post-approval requirements that the FDA has imposed as part of the approval process.

We will be required to report certain adverse reactions and manufacturing problems to the FDA, provide updated safety and efficacy information, and comply with requirements concerning advertising and promotional labeling requirements.

Manufacturers of our products are required to register their establishments with the FDA and certain state agencies and are subject to periodic announced or ad hoc inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP regulations, which impose certain procedural and documentation requirements upon these manufacturers.

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Once a marketing approval is granted for our product candidate, the FDA may withdraw the approval if compliance with regulatory requirements is not maintained or if problems occur after our product reaches the market.

Later discovery of previously unknown problems with our product, including adverse events of unanticipated severity or frequency, issues with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information, imposition of post-marketing studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS program.

Other potential consequences of a failure to comply with regulatory requirements include:

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The FDA strictly regulates marketing, labeling, advertising, and promotion of licensed and approved products that are placed on the market.

Pharmaceutical products may be promoted only for the approved indications and in accordance with the provisions of the approved label.

Pharmaceutical products may be promoted only for the approved indications and in accordance with the provisions of the approved labeling.

Orphan Drug Designation

Orphan drug designation may be available for drugs that are intended for rare diseases or conditions, defined as (i) a disease or condition that affects fewer than 200,000 individuals in the United States or (ii) a disease or condition that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making available a biologic for the disease or condition will be recovered from sales of the product in the United States.

In June 2019, the FDA’s policy, based on its regulations, see 21 C.F.R.

§316.3(b), was challenged by a pharmaceutical company that argued that once an orphan drug is approved for a disease or condition, the FDA may not approve another drug for the same disease or condition, even if for different uses or indications that the FDA has not approved.

On appeal, in December 2021, the U.S.

Court of Appeals for the Eleventh Circuit reversed the lower court’s decision and agreed with the position of the pharmaceutical company that challenged the FDA.

Despite this loss, in January 2023, FDA stated its intent to continue to apply its regulations tying the applicability of the orphan drug exclusivity to the specific uses or indications, rather than diseases or conditions.

It is possible that, in the future, Congress or the FDA may further update and revise the law and policies on this issue.

In addition, other financial incentives, such as tax credits, may be available.

Orphan drug designation is available for drugs that are intended for rare diseases or conditions, defined as (i) a disease or condition that affects fewer than 200,000 individuals in the United States or (ii) a disease or condition that affects more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making available a biologic for the disease or condition will be recovered from sales of the product in the United States.

If a drug becomes the first drug that is approved for the same indication for which the FDA has granted the designation, the drug will be entitled to exclusivity, which means the FDA may not approve any other application to market the same drug for the same orphan indication for a period of seven years following the date of our product’s marketing approval, except in certain circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity by means of greater effectiveness, greater safety, or providing a major contribution to patient care, or in instances of drug supply issues.

In the case of a biological product, sameness is based on the principal molecular features of the product.

Orphan drug exclusivity does not prevent FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition.

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To obtain an orphan drug designation, we must make a request before submitting our BLA for a particular product candidate.

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Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The FDA has granted orphan drug designation to CB-010 for the treatment of FL and to CB-011 for the treatment of MM.

In addition, other financial incentives, such as tax credits or exemption from the BLA application fee, may be available.

Pediatric Studies and Exclusivity

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The FDA may, on its own initiative or at the request of the sponsor, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements, under specified circumstances.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.

Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the non-patent and orphan exclusivity.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation except a product with a new active ingredient that is a molecularly targeted cancer product intended for the treatment of an adult cancer and directed at a molecular target determined by the FDA to be substantially relevant to the growth or progression of a pediatric cancer.

Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing non-patent regulatory exclusivity, including orphan drug exclusivity.

This six-month exclusivity may be granted if pediatric data is submitted that sufficiently responds to a written request from the FDA for such data.

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The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (“Affordable Care Act”) includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product in the United States.

Starting in 2015, the FDA commenced licensing biosimilars under the BPCIA, and there are currently numerous biosimilars approved in the United States and Europe.

For the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and proposed biosimilar product in terms of safety, purity, and potency.

Starting in 2015, the FDA commenced licensing biosimilars under the BPCIA, and there are currently numerous biosimilars approved in the United States as well as a number of interchangeable biosimilar products.

For the FDA to approve a biosimilar product as interchangeable with a reference product, the agency must find that the biosimilar product can be expected to produce the same clinical results as the reference product, and, for products administered multiple times, that the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Even after the FDA approves a biosimilar product, the product, its manufacturing processes, post-approval clinical data, labeling, advertising, and promotional activities for the product will be subject to continuous requirements of and review by the FDA or other regulatory authorities.

These requirements include submissions of safety and other post-marketing information and reports, including mandatory post-marketing safety reporting;

These requirements include submissions of safety and other post-marketing information and reports, including mandatory post-

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marketing safety reporting;

registration and listing requirements;

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The FDA may not approve a biosimilar product until 12 years from the date on which the reference product was approved.

Even if a product is considered to be a reference product eligible for exclusivity, another company could market a competing version of that product if the FDA approves a full BLA for such product containing our own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity, and potency of the product.

Even if a product is considered to be a reference product eligible for exclusivity, another company could market a competing version of that product if the FDA approves a full BLA for such product containing our own nonclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity, and potency of the product.

Patent Term Extension

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Regulation and Procedures Governing Approval of Medicinal Products in Other Countries

governing, among other things, clinical trials, marketing authorization, post-authorization requirements, commercial sales, import and export, reimbursement, and distribution of products.

In order to market any product outside of the United States, we must also comply with numerous and comprehensive regulatory requirements of other countries and jurisdictions, regarding quality, safety, and efficacy, and governing, among other things, clinical trials, marketing authorization, post-authorization requirements, commercial sales, import and export, reimbursement, and distribution of products.

Whether or not we obtain FDA approval for our product candidates, we will need to obtain the necessary approvals from health regulatory authorities in other countries or jurisdictions before we can initiate clinical trials or marketing of our products in those countries or jurisdictions.

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Foreign Corrupt Practices Act of 1977, as amended (“FCPA”), and similar anti-bribery or anti-corruption laws, regulations, and rules of other countries in which we may choose to operate, could apply to our international activities.

Anti-corruption laws generally prohibit companies and their employees, agents, contractors, and other collaborators from authorizing, promising, offering, or providing, directly or indirectly, improper payments or anything else of value to recipients in the public or private sector in order to influence action.

Anti-corruption laws generally prohibit companies and their employees and certain other third parties from authorizing, promising, offering, or providing, directly or indirectly, improper payments or anything else of value to recipients in the public or private sector in order to influence action.

The FCPA also requires public companies to make and keep books and records that accurately and fairly reflect the transactions of the company and to devise and maintain an adequate system of internal accounting controls.

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Treasury Department’s Office of Foreign Assets Controls could apply to any international activities we may undertake.

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Coverage, Pricing, and Reimbursement

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Even if any product candidates we may develop obtain approval, sales of such product candidates will depend, in part, on the extent to which third-party payors, including government healthcare programs in the United States, such as Medicare and Medicaid, commercial health insurers, and managed care organizations provide coverage and establish adequate reimbursement levels for such product candidates.

In general, factors a payor considers in determining coverage and reimbursement are based on whether the product is:

In general, factors payors consider in determining coverage and reimbursement are based on whether the product is:

• a covered benefit under its health plan;

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Some countries may require the completion of additional testing or studies that compare the cost effectiveness of a particular biological product to currently available treatments, or so-called health technology assessments, in order to obtain reimbursement or pricing approval.

The EU HTA Regulation 2021/2282 became effective in January 2022 and aims to harmonize clinical and scientific aspects of HTA across the EU.

However, it will only begin to apply from January 2025 and will have a phased implementation.

The EU HTA Regulation 2021/2282 became effective in January 2022, is applicable from January 2025 with a phased implementation until 2030, and aims to harmonize clinical and scientific aspects of HTA across the EU.

Some countries, including several EU member states, set prices and reimbursement for biological products, with limited participation from the marketing authorization holders.

For example, the EU provides options for its member states to restrict the range of biological products for which their national health insurance systems provide reimbursement and to control the prices of biological products for human use.

For example, the EU provides options for its member states to restrict the range of biological products for which their national health insurance systems provide reimbursement and to

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control the prices of biological products for human use.

EU member states may approve a specific price for a biological product or may instead adopt a system of direct or indirect controls on the profitability of the company providing the biological product.

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False Claims Act, and civil monetary penalties laws, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false, fictitious, or fraudulent or knowingly making, using, or causing to be made or used a false record or statement to avoid, decrease, or conceal an obligation to pay money to the federal government.

In addition, the government may assert that a

claim including items and services resulting from a violation of the AKS or FDA promotional standards constitutes a false or fraudulent claim for purposes of the U.S.

In addition, the government may assert that a claim including items and services resulting from a violation of the AKS or FDA promotional standards constitutes a false or fraudulent claim for purposes of the U.S.

False Claims Act;

federal Beneficiary Inducement Statute, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value, with limited exceptions, to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of items or services reimbursable by a federal or state health program;

Beneficiary Inducement Statute, which prohibits, among other things, the offering or giving of remuneration, which includes, without limitation, any transfer of items or services for free or for less than fair market value, with limited exceptions, to a Medicare or Medicaid beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of items or services reimbursable by a federal or state health program;

Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), and their respective implementing regulations (collectively “HIPAA”), which imposes criminal and civil liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private payors, or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services;

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Physician Payments Sunshine Act, or Open Payments program, created under the Affordable Care Act, which requires certain manufacturers of drugs, devices, biologics, and medical supplies to report annually to the Centers for Medicare & Medicaid Services (“CMS”) information related to payments, including certain product development activities such as clinical trials, and other transfers of value made by that entity to covered recipients, currently defined to include doctors, dentists, optometrists, podiatrists, chiropractors, teaching hospitals, physician assistants, nurse practitioners, and certain other healthcare providers and requires certain manufacturers and applicable group purchasing organizations to report ownership and investment interests held by physicians or their immediate family members;

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price reporting laws, which require companies to calculate and report complex pricing metrics in an accurate and timely manner to government programs.

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In the United States, states are constantly amending existing laws, requiring attention to frequently changing regulatory requirements.

Furthermore, additional federal measures and efforts have been made to increase price transparency for drug pricing, modify the government program reimbursement methodologies, and provide additional ways for the government to attempt to lower drug prices.

For example, the Inflation Reduction Act of 2022 imposes inflation rebates on drug manufacturers for products reimbursed under Medicare Parts B and D if the prices of those products increase at a rate greater than inflation;

implements changes to the Medicare Part D benefit that, beginning in 2025, will cap annual out-of-pocket spending at $2,000 while imposing new discount obligations for pharmaceutical manufacturers;

and, beginning in 2026, establishes a “maximum fair price” for a selected list of pharmaceutical and biological products covered under Medicare Parts B and D following a price negotiation process with the Centers for Medicare and Medicaid Services.

These provisions are not likely to affect our operations in the near term since our product candidates have not received marketing approval.

There have also been other administrative efforts to lower drug prices.

In 2022, Executive Order on Lowering Prescription Drug Costs for Americans was issued and directed the secretary of the Department of Health and Human Services to “consider whether to select for testing by the Innovation Center new health care payment and delivery models that would lower drug costs and promote access to innovative drug therapies for beneficiaries enrolled in the Medicare and Medicaid programs, including models that may lead to lower cost-sharing for commonly used drugs and support value-based payment that promotes high-quality care.” By 2029, up to 60 pharmaceutical products will be subject to price negotiation.

There are likely to be additional changes in the future by federal, state, and foreign governments, and predicting such changes and responding to such changes in a timely manner may be challenging.

Healthcare Reform

A primary trend in the U.S.

healthcare industry and elsewhere is cost containment.

There have been a number of federal and state proposals during the last few years that apply to the pricing of pharmaceutical and biopharmaceutical products, limit coverage and reimbursement for drugs and other medical products, require substitution of generic products, standardize access to third-party insurance coverage, and address government control and other changes to the healthcare system in the United States.

The federal and state governments may pass legislation designed to reduce the cost of healthcare, and future amendments and new proposals may affect the commercialization of any of our product candidates in ways that we cannot foresee.

For example, in March 2010, the U.S.

Congress enacted the Affordable Care Act, which, among other things, included changes to the coverage and payment for products under government health care programs.

Among the provisions of the Affordable Care Act that may be of importance to our potential product candidates are:

• an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic products, apportioned among these entities according to their market share in certain government healthcare programs, although this fee would not apply to sales of certain products approved exclusively for orphan indications;

• expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer

price” for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices and extending rebate liability to prescriptions for individuals enrolled in Medicare Advantage plans;

• established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a 70% point-of-sale-discount off the negotiated price of applicable products to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient products to be covered under Medicare Part D, increased pursuant to the Bipartisan Budget Act;

• the establishment of a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

• the establishment of the Center for Medicare and Medicaid Innovation within CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription product spending;

• introduction of a new average manufacturer price definition for biologics and drugs that are inhaled, infused, instilled, implanted, or injected and not generally dispensed through retail community pharmacies;

• increase in the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and expansion of rebate liability from fee-for-service Medicaid utilization to include the utilization of Medicaid managed care organizations as well;

• establishment of a branded prescription drug fee that pharmaceutical manufacturers of branded prescription drugs must pay to the federal government;

• expansion of the list of covered entities eligible to participate in the 340B drug pricing program;

• expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories for individuals with income at or below 133% of the federal poverty level, thereby potentially increasing manufacturers’ Medicaid rebate liability;

• creation of a licensure framework for follow on biologic products.

Recently, CMS finalized regulations that give states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the Affordable Care Act for plans sold through such marketplaces.

It is unclear what type of impact, if any, efforts such as this will have on our business in the future.

Other legislative changes have been proposed and adopted since the Affordable Care Act was enacted.

The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, including hospitals, imaging centers, and cancer treatment centers, and increased from three to five years the statute of limitations period for the government to recover non-fraudulent overpayments to providers.

New laws may result in additional reductions in Medicare and other healthcare funding, which may materially adversely affect customer demand for and affordability of our product candidates and, accordingly, our business, financial condition, results of operations, and prospects.

Additional changes that may affect our business include the expansion of new programs such as Medicare payment for performance initiatives for physicians under the Medicare Access and CHIP Reauthorization Act of 2015, which first affected physician payment in 2019.

At this time, it is unclear how the introduction of the Medicare quality payment program will impact overall physician reimbursement.

In addition, in August 2022, the Inflation Reduction Act of 2022 implemented substantial changes to the Medicare program, including drug pricing reforms and changes to the Medicare Part D benefit design.

Other legislative measures have also been enacted that may impose additional pricing and product development pressures on our business.

For example, on May 30, 2018, the Right to Try Act, was signed into law.

The law, among other things, provides a federal framework for certain patients to access certain IND products that have completed a phase 1 clinical trial and that are undergoing investigation for FDA approval.

Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

There is no obligation for a drug manufacturer to make its drug product candidates available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.

Also, effective January 1, 2023, the Inflation Reduction Act of 2022 instituted a price cap on

insulin reimbursed through Medicare's prescription drug benefit, and it is possible that, in the future, additional drugs and biologics could be targeted for price caps.

We expect that additional foreign, federal, and state healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in limited coverage and reimbursement and reduced demand for our products, post-approval, or additional pricing pressures.

Individual states in the United States have also become increasingly active in enacting legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

We cannot predict what healthcare reform initiatives may be adopted in the future.

Additional federal, state, and foreign legislative and regulatory developments are likely, and we expect ongoing initiatives to increase pressure on drug pricing.

Such reforms could have an adverse effect on anticipated revenues from product candidates and may affect our overall financial condition and ability to develop product candidates.

In the United States, there have been, and continue to be, proposals by the federal government, state governments, regulators and third-party payors to control or manage the increased costs of health care and, more generally, to reform the U.S.

healthcare system.

The pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives.

For example, in March 2010, the Affordable Care Act (“ACA”) was enacted, which intended to broaden access to health insurance, reduce or constrain the growth of healthcare spending, enhance remedies against fraud and abuse, add new transparency requirements for the healthcare and health insurance industries, impose new taxes and fees on the health industry and impose additional health policy reforms, substantially changed the way healthcare is financed by both governmental and private insurers, and significantly impacts the U.S.

pharmaceutical industry.

Healthcare reforms that have been adopted, and that may be adopted in the future, could result in further reductions in coverage and levels of reimbursement for pharmaceutical products, increases in rebates payable under U.S.

government rebate programs and additional downward pressure on pharmaceutical product prices.

Several healthcare reform proposals culminated in the enactment of the Inflation Reduction Act (the “IRA”) in August 2022, which, among other things, eliminated, beginning in 2025, the coverage gap under Medicare Part D by significantly lowering the enrollee maximum out-of-pocket costs and requiring manufacturers to subsidize, through a newly established manufacturer discount program, 10% of Part D enrollees’ prescription costs for brand drugs below the out-of-pocket limit, and 20% once the out-of-pocket limit has been reached.

The IRA also allows HHS to directly negotiate the selling price of a statutorily specified number of drugs and biologics each year that CMS reimburses under Medicare Part B and Part D.

The negotiated price may not exceed a statutory ceiling price.

Only high-expenditure single-source

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biologics that have been approved for at least 11 years (seven years for single-source drugs) are eligible to be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.

For 2026, the first year in which negotiated prices become effective, CMS selected 10 high-cost Medicare Part D products in 2023, negotiations began in 2024, and the negotiated maximum fair price for each product has been announced.

CMS has selected 15 additional Medicare Part D drugs for negotiated maximum fair pricing in 2027.

For 2028, an additional 15 drugs, which may be covered under either Medicare Part B or Part D, will be selected, and for 2029 and subsequent years, 20 Part B or Part D drugs will be selected.

A drug or biological product that has an orphan drug designation for only one rare disease or condition will be excluded from the IRA’s price negotiation requirements, but will lose that exclusion if it receives designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation.

The IRA also imposes rebates on Medicare Part B and Part D drugs whose prices have increased at a rate greater than the rate of inflation.

The IRA also extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to regulation, for the initial years.

Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties.

These provisions may be subject to legal challenges.

For example, the provisions related to the negotiation of selling prices of high-expenditure single-source drugs and biologics have been challenged in multiple lawsuits brought by pharmaceutical manufacturers.

The outcome of these lawsuits is uncertain, and some IRA drug discount provisions have not been challenged in litigation.

Thus, while it is unclear how the IRA will be implemented, it will likely have a significant impact on the pharmaceutical industry and the pricing of our products and product candidates.

It is unclear what policies the new Administration will advance with respect to IRA implementation and other drug pricing proposals.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access, and marketing cost disclosure and transparency measures, and in some cases, designed to encourage importation from other countries and bulk purchasing.

Additional Regulations

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Employee and Human Capital Resources

As of March 1, 2024, we have 158 employees.

Of these employees, 77% are primarily engaged in research and development activities.

None of our employees is represented by a labor union or party to a collective bargaining agreement.

We consider our relationship with our employees to be good.

We have attracted a talented group of experienced scientists, drug development experts, and company builders as part of a passionate team of employees.

Our team includes experts in genome-editing technologies, cellular engineering, protein science, computational biology, genome sequencing and analysis, structural biology, chemistry, biometrics, translational medicine, pharmacovigilance, process development, analytical development, medical affairs, clinical operations and development, regulatory affairs, and quality assurance and control.

Our team of employees includes some of the scientists who invented the technologies we use today in our research and product development and who continue to drive innovation.

Workforce Demographics

As of March 1, 2025, we had 147 total employees, all of which were full-time.

Of our employees, 39 hold Ph.D., M.D., and/or Pharm.D.

degrees, and 107 are engaged in research, development, and technical operations.

Most of our employees are located in Berkeley, California.

Our employees are not represented by labor unions or covered by collective bargaining agreements.

We believe that our employee morale is healthy and consider our relationship with our employees to be good.

Talent Acquisition, Development, and Total Rewards

We recognize that attracting, developing, and retaining talent at all levels is vital to our continued success.

Our employees are our greatest asset, and we aim to create an equitable, inclusive, and collaborative environment with the overall goal of engaging our workforce to support our current pipeline, develop new technologies, and support future business goals, while protecting the long-term interests of our stockholders.

We live by our core values:

We have implemented a comprehensive talent strategy that motivates our employees to perform to the best of their abilities and to achieve our objectives.

We are committed to providing a competitive and comprehensive total rewards program that includes market-aligned salaries, performance-based incentives, long-term equity grants, and comprehensive benefits, including health and wellness programs, retirement savings plan (401k), an employee stock purchase plan (ESPP), and paid time off.

We invest in employee learning and development by identifying and providing training and development programs, tuition reimbursement, and cross-training in areas of interest beyond hired roles.

Employees have access to ongoing learning opportunities to enhance their skills and advance their careers.

We understand the importance of goal setting and ongoing career development conversations.

We require our managers and employees to play an active role in the performance management process.

Our performance management

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process is designed to increase clarity and accountability for roles and responsibilities, strengthen communication, and build trust, all while championing personal and professional growth, learning, and success.

Great teamwork is a critical foundation for Caribou.

Our peer-to-peer rewards and recognition program helps us maintain a culture of recognition and teamwork by offering various options for our employees and managers to recognize and reward colleagues across the organization.

We plan to continue to refine our efforts related to optimizing our use of human capital as we grow, including improvements in the way we hire, develop, reward, and retain employees.

The Herd at Caribou

Our employees are our greatest asset, and we aim to create an inclusive and collaborative environment with the overall goal of engaging our workforce to support our current pipeline, develop new technologies, and support future business goals, while protecting the long-term interests of our stockholders.

Our culture is built around our core values:

we are driven by patient needs, innovation is in our chRDNA, together we are stronger, and integrity and ethics guide our decision making.

We have built a culture where employees are empowered, their ideas are taken seriously, and their contributions are recognized.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, motivating, and engaging our existing and future employees.

The principal purposes of our equity and cash incentive plans are to attract, retain, and recognize employees through grants of stock-based compensation awards and payments of performance-based cash bonus awards, which motivate our employees to perform to the best of their abilities and achieve our objectives.

We are committed to providing a competitive and comprehensive benefits package to our employees.

Our benefits package provides a balance of overall protection along with the flexibility to meet the individual health and wellness needs of our employees.

We plan to continue to refine our efforts related to optimizing our use of human capital as we grow, including improvements in the way we hire, develop, reward, and retain employees.

Diversity, Equity, and Inclusion

We are committed to cultivating, fostering, and preserving a culture of diversity, equity, and inclusion (“DEI”).

We foster an inclusive environment through respect, collaboration, and candid communication.

We embrace and encourage

differences in age, color, disability, ethnicity, family or marital status, gender identity or expression, language, national origin, culture or customs, physical and mental ability, political affiliation, race, religion, sexual orientation, socio-economic status, veteran status, and other characteristics that make our employees unique.

We embrace differences in experience and background, and we welcome a diversity of opinions when making decisions.

We would not be who we are today without the diversity of our team.

As of March 1, 2024, 51% of our employees identify as female.

The ratio of men to women is fairly balanced at each level of our organization;

as an example, 47% of our director-level and above employees identify as female.

In addition, as of March 1, 2024, 46% of our employees identify as a member of at least one underrepresented group, with 27% identifying as Asian, 6% identifying as Hispanic or Latinx, 3% identifying as Black or African American, and 9% identifying as a member of other underrepresented groups or as a member of two or more underrepresented groups;

furthermore, 35% of our director-level and above employees identify as a member of at least one underrepresented group.

Our employees span multiple age brackets and bring their unique perspectives and experiences to our organization.

As of March 1, 2024, the average age of our employees is 40 years old, and 46% of our workforce is 40 years of age or older.

Although we are proud of our efforts and metrics to date, we recognize that there is still more work to be done until the diversity of our workforce matches the diversity of the San Francisco Bay Area.

To champion our efforts in this area, in 2021 we formed an Inclusion Committee comprised of employees from various departments, backgrounds, and levels within our organization.

The Inclusion Committee emphasizes our commitment to the importance of DEI and the responsibility of our employees to treat others with dignity and respect at all times.

All employees are provided diversity awareness training and unconscious bias training to enhance their knowledge to fulfill this responsibility, in addition to mandatory sexual harassment prevention training.

The Inclusion Committee works to identify gaps, respond to feedback provided by peers and present suggestions on our hiring and retention practices and policies to encourage and enforce an environment in which all employees feel included and empowered to achieve their best potential.

Management has committed time and resources for this ongoing initiative.

Additionally, we support our employee resource groups (“ERGs”), currently focusing on LGTBQ+, Asian-American Hawaiian Pacific Islanders, mental health, and parenting, which allows our employees to connect in ways that are meaningful to their individual needs and which provide a platform for obtaining resources and support at our company.

We at Caribou refer to ourselves as “the herd.” We encourage and value social interactions among the herd.

We hold bi-monthly herd meetings and quarterly on-site events to strengthen our culture and find different ways to interact.

Some of these events include contributing to the Alameda Food Bank and participating in San Francisco Bay clean-up events.

We offer “fun runs,” yoga in a hybrid format, and have local gym facilities available for our Berkeley employees.

As we continue to grow, we will find more opportunities to connect our teams, taking into account our different functions and locations, while focusing on building a culture that is driven by our mission to develop innovative, transformative therapies through novel genome editing for patients with devastating diseases.

We regularly conduct engagement surveys and use the feedback to enhance our workplace culture.

Our well-being initiatives include mental health resources and flexible work arrangements to support our employees’ overall health and productivity.

We have established a culture advisory group comprised of cross-functional representatives from various geographic locations.

Based on feedback from focus groups and the culture advisory group, along with the results of employee surveys, we have focused on highlighting how our daily work connects to our corporate values, connecting teams to other functions, and helping employees understand how decisions that impact them or their roles are made.

Survey results demonstrate that employees feel more connected and are committed and excited to come to work, increasing overall engagement.

We expect all employees to observe the highest levels of business ethics while delivering the highest levels of performance.

We encourage employees to speak up and raise questions and concerns promptly about any situation that may violate our Code of Business Conduct, Scientific and Data Integrity, and Ethics or any other corporate policy.

We believe that it is beneficial for employees to raise concerns so that we may consider them carefully and address them appropriately.

We seek to promote an environment that fosters honest communications about matters of conduct related to our business activities, whether that conduct occurs within our company or involves one of our third-party suppliers, service providers, or collaborators.

We work diligently to make clear that management is prepared to address any reported violations and to ensure that it is known that any form of retaliation is prohibited.

In addition, we have an easily accessible hotline available to employees wishing to report complaints anonymously.

Involvement in Our Community

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The City of Berkeley requires companies with 10 or more employees to have a commuter benefits program in place, and we offer pre-tax commuter benefits to ride public transportation, which is connected to our facility through various free shuttle services.

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Additionally, we provide bicycle vouchers to employees who bike to work and have bike repair tools on site as well as bike storage areas, and our employees have access to electric vehicle charging stations.

Our facility is equipped with water stations that filter water to discourage the use of plastic bottles.

All refuse generated at our company is sorted among recycle, compost, and landfill.

All refuse generated at our facility is sorted among recycle, compost, and landfill.

We have moved to electronic documentation and files in most functions.

The Herd at Caribou

We at Caribou refer to ourselves as “the herd.” We encourage and value social interactions among the herd.

We hold weekly herd meetings, monthly happy hours, and quarterly events to strengthen our culture and find different ways to interact.

Some of these events include contributing to the Alameda Food Bank and participating in San Francisco Bay clean-up events.

Weather permitting, we sponsor regular “fun runs” for employees to either run or walk to the shoreline or in the Berkeley hills.

We offer yoga in a hybrid in-person/virtual format for all our employees, regardless of location.

As we continue to grow, we will find more opportunities to connect our teams, taking into account our different functions and

locations, while focusing on building a culture that is driven by our mission to develop innovative, transformative therapies through novel genome editing for patients with devastating diseases.

Workforce Health and Safety

Workplace safety is a priority for us.

To maintain a safe and healthy workplace, we have implemented Environment, Health, and Safety (“EHS”) initiatives that focuses on key risk mitigation programs to identify, assess, and correct hazards.

We also have a safety training program that is designed for employees to be assigned the appropriate training to understand how to safely perform their duties.

Information Available on the Internet

Investors and others should note that we announce material information to our investors using our investor relations website (https://cariboubio.com/investors), our filings with the Securities and Exchange Commission (“SEC”), press releases, public conference calls, and webcasts.

Investors and others should note that we announce material information to our investors using our investor relations website (https://cariboubio.com/investors), our filings with the U.S.

Securities and Exchange Commission (“SEC”), press releases, public conference calls, and webcasts.

We use these channels to communicate with the public about our company, our business, our product candidates and other matters.

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The materials we file with or furnish to the SEC are also available at http://www.sec.gov.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business