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Item 1. Business

2024-03-11 compared with 2023-03-09 · 389 added, 441 removed, 805 unchanged (51% of the section changed)

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”) technologies, enables high-precision genome editing to develop cell therapies that are armored to improve antitumor activity.

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 multiple allogeneic cell therapies for the treatment of hematologic malignancies and solid tumors.

Our therapies are directed at established tumor 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).

We use our chRDNA technologies to armor our cell therapies’ antitumor activity by using tailored armoring strategies, such as checkpoint disruption, immune cloaking, or a combination of these two strategies.

Our pipeline includes allogeneic cell therapies from our CAR-T and CAR-NK platforms.

We currently are advancing four wholly owned programs for the treatment of hematologic malignancies and solid tumors.

Additionally, under a collaboration agreement with AbbVie Manufacturing Management Unlimited Company (“AbbVie”), we are developing two CAR-T cell therapies for AbbVie.

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).

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:

1 Phase 3 may not be required if Phase 2 is pivotal

* Also known as CD371

3 AbbVie has an option to include two additional CAR-T cell programs

We are developing a pipeline of allogeneic immune cell therapies for hematologic malignancies and solid tumors.

Our Clinical Programs

Our lead product candidate, CB-010, is an allogeneic CAR-T cell therapy that is, to our knowledge, 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 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.

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CB-010 is being evaluated in our ongoing ANTLER phase 1 clinical trial in patients with relapsed or refractory B cell non-Hodgkin lymphoma (“r/r B-NHL”).

As reported in 2022, the first cohort contained six patients who have been dosed with CB-010 at dose level 1 (40x10 6 CAR-T cells).

In this first cohort of patients, CB-010 was generally well tolerated with adverse events as expected for anti-CD19 CAR-T cell therapies, and we observed complete responses in three of six patients that lasted at least six months.

As reported in 2022, the second cohort enrolled three patients at dose level 2 (80x10 6 CAR-T cells), and we are currently enrolling patients at dose level 3 (120x10 6 CAR-T cells).

We plan to provide an ANTLER update in the second half of 2023.

CB-010 has received Regenerative Medicine Advanced Therapy (“RMAT”) designation for relapsed or refractory large B cell lymphoma (“LBCL”), fast track designation for r/r B-NHL, and orphan drug designation for follicular lymphoma (“FL”) from the U.S.

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.

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-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”), and we are currently recruiting patients at dose level 1 (50x10 6 CAR-T cells).

Our Preclinical Programs

Our 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-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”).

CB-012 is being evaluated in investigational new drug (“IND”)-enabling studies to support a planned IND application submission for relapsed or refractory AML (“r/r AML”) in the second half of 2023.

Additionally, we are developing allogeneic CAR-NK cell therapies derived from genome-edited induced pluripotent stem cells (“iPSCs”) for the treatment of solid tumors.

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

CB-020 is our first CAR-NK cell therapy and we have selected receptor tyrosine kinase like orphan receptor 1 (“ROR-1”) as the tumor cell surface target.

AbbVie Programs under Collaboration Agreement

In February 2021, we entered into a Collaboration and License Agreement (as amended, the “AbbVie Agreement”) with AbbVie to develop two CAR-T cell therapies for AbbVie.

We view this collaboration as an external recognition of the potential for our Cas12a chRDNA genome-editing technology to significantly improve genome-editing specificity and efficiency.

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

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

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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.

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.

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

Doudna, Ph.D., who was a co-recipient of the 2020 Nobel Prize in Chemistry for the development of CRISPR-Cas9 as a method for genome editing;

Martin Jinek, Ph.D., Assistant Professor at the University of Zurich in the Department of Biochemistry;

Martin Jinek, Ph.D., Associate Professor at the University of Zurich in the Department of Biochemistry;

James Berger, Ph.D., Professor in the Department of Biophysics and Biophysical Chemistry at the Johns Hopkins University School of Medicine;

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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, T cell metabolism and tumor interactions, and NK cell biology.

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.

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

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

Canonical genome editing occurs in two steps, as shown in figure 2 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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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 double-stranded break (“DSB”) in chromosomal DNA at a desired location.

The cell will seal the break by an error-prone process called non-homologous end joining (“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 homology-directed repair (“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 their agility and their 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 that are in preclinical research or clinical development.

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.

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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.

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Our CRISPR Hybrid RNA-DNA (chRDNA) Technologies

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• Specificity:

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

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.

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

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Our Cas12a chRDNA technology mediates high rates of site-specific insertion.

High efficiency Cas12a chRDNA editing yields >60% of the T cell population possessing 2 gene inserts and 2 gene knockouts, thus having all 4 intended edits.

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

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

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

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

See figures 5 and 6 below.

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

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

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

However, the chRDNA guides, in contrast to the all-RNA guides, result in minor to no detectable off-target editing.

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.

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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 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 homology-directed repair pathway.

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

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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.

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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 and CAR-NK cell products with next-generation capabilities and approaches.

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 and CAR-NK cells are critical to achieving long-term efficacy.

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.

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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 products:

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.

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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.

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

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 for any eligible patient at any time, which significantly shortens wait times and avoids the need to undergo leukapheresis and to wait for a manufacturing slot, thereby reducing patient burden.

In addition, allogeneic cell therapies may offer an opportunity for repeated dosing in patients with significant tumor burden.

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.

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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 avoid the potential need for bridging therapy.

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 bespoke batch of cell therapy.

• Healthy donor cells engineered with genome-editing strategies enhanced antitumor activity.

• 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 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

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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 solid tumors, and our chRDNA technologies offer broad potential applications longer-term.

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 antitumor activity.

Our chRDNA technologies enable us to design allogeneic cell therapies with the potential to achieve enhanced antitumor activity through the use of tailored armoring strategies, including (i) checkpoint disruption, 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.

• 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.

We are advancing the clinical development of two product candidates, CB-010 for r/r B-NHL and CB-011 for r/r MM.

CB-010 is directed to the CD19 tumor antigen, and CB-011 is directed to the BCMA tumor 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 two clinical-stage allogeneic CAR-T cell therapies.

CB-010 is being evaluated in our ongoing ANTLER phase 1 clinical trial and CB-011 is being evaluated in our recently initiated CaMMouflage phase 1 clinical trial.

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.

• 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,

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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 IND-enabling studies to support a planned IND application submission for r/r AML in the second half of 2023.

• Developing CAR-NK cell therapies for the treatment of solid tumors by leveraging our iPSC-derived NK cell (“iNK”) therapy platform.

We believe NK cells are a promising cell type for the treatment of solid tumors and metastases.

We have developed robust protocols to edit iPSCs and to differentiate and expand them into NK cells that have antitumor potential.

We intend to pursue targeting multiple types of solid tumors for which there is high unmet medical need.

Our anti-ROR1 CB-020 product candidate is in preclinical development.

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 technologies protected by a robust IP portfolio.

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 executed a strategic license and collaboration agreement with AbbVie in February 2021 to develop two allogeneic CAR-T cell therapies for AbbVie using our Cas12a chRDNA genome-editing and cell therapy technologies.

In the future, we plan to seek additional opportunities with select collaborators as appropriate to accelerate our ability to develop therapeutics to address significant unmet medical need.

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, cell therapies derived from genome-edited iPSCs, 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 through collaborations.

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

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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.

• Expanding into solid tumors:

We are also focused on developing genome-edited, off-the-shelf CAR-NK cell therapies for the treatment of solid tumors.

In our preclinical studies to date, we have observed that our chRDNA technologies can precisely edit iPSCs, and we can generate genome-edited iNKs that are armored to enhance tumor targeting, allogeneic CAR-NK cell survival, and persistence of antitumor activity.

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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 tumor antigen engagement via their respective CAR.

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.

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(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 platform where improved targeting, CAR-NK cell survival, and enhancement of antitumor activity is thought to be key.

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 in T cells.

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 knock out the PDCDI gene to eliminate PD-1 expression from the CAR-T cell surface, thereby preventing PD-1/PD-L1-mediated exhaustion.

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 allogeneic CAR-T cell therapy.

Immune-Cloaking Strategy

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

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

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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 allogeneic CAR-T and CAR-NK cell therapies focused on the treatment of hematologic malignancies and solid tumors.

Additionally, under the AbbVie collaboration, we are developing two CAR-T cell therapies for AbbVie.

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.

1 Phase 3 may not be required if phase 2 is pivotal

* Also known as CD371

3 AbbVie has an option to include two additional CAR-T cell programs

We are developing a pipeline of allogeneic immune cell therapies for hematologic malignancies and solid tumors.

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

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 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.

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 CD19-specific CAR and the TCR and PD-1 are knocked out.

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

TRAC knockout:

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Site-specific insertion of the anti-CD19 CAR:

We insert the CD19-targeted CAR into the TRAC gene by AAV6 transduction and homology directed repair.

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 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 PD-L1.

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.

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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 and CAR-T cell-mediated antitumor responses.

Target Indication

We are developing CB-010 for the treatment of r/r B-NHL.

Non-Hodgkin lymphoma is the most common hematologic malignancy with an estimated 80,470 cases, or 4% of all cancers diagnosed in the United States in 2022 according to the National Cancer Institute SEER database.

B-NHL makes up 80 to 85% of those non-Hodgkin lymphoma cases.

Approximately 34% of B-NHL cases are considered relapsed or refractory.

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B-NHL is a heterogeneous malignancy that is monoclonal in nature and arises in B lymphocytes.

The disease can often be traced to specific stages in lymphoid maturation.

Most malignant lymphocytes derive from mature B cells or from lymphocytes of germinal center origin.

The malignant cells have acquired the ability to proliferate, evade the host immune response, and avoid cellular apoptosis.

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.

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.

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

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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.

Thus, there remains a significant unmet medical need in r/r B-NHL.

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

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.

The patient population includes individuals for whom at least two lines of chemo- and/or immunotherapy have failed or refractory patients who have rapidly progressed after their first treatment.

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.

The eligible patient population in the trial includes the following aggressive B-NHL subtypes:

diffuse large B cell lymphoma (“DLBCL”);

high grade B cell lymphoma (“HGBL”);

transformed follicular lymphoma (“tFL”);

primary mediastinal large B cell lymphoma (“PMBCL”);

follicular lymphoma (“FL”) that is aggressively behaving with progression of disease within 24 months (“POD24”), which is a measure of high risk disease;

marginal zone lymphoma (“MZL”);

and mantle cell lymphoma (“MCL”).

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 has been previously used with allogeneic 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 adverse events defined as dose-limiting toxicities (“DLTs”) within 28 days after CB-010 infusion, as well as the overall objective response rate and the identification of the recommended phase 2 dose (“RP2D”), as shown in figure 11 below.

Our ANTLER phase 1 clinical trial is being conducted in two parts and we estimate enrolling up to approximately 50 patients 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-010.

Part B is the expansion portion where patients will receive CB-010 at the dose or doses determined in Part A.

In 2022, CB-010 was granted RMAT designation for LBCL, Fast Track designation for r/r B-NHL, and Orphan Drug designation for FL.

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maximum tolerated dose;

recommended phase 2 dose

1 Aggressively behaving, with POD24 (high risk)

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.

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”).

2 LBCL subtypes include:

DLBCL NOS, HGBL, transformed DLBLC from FL or MZL, and PMBCL.

3 Clin Cancer Res.

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

Clinicaltrials.gov NCT#04637763

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.

Part B is an expansion portion where patients will receive CB-010 at the dose or doses determined in Part A.

During dose escalation, our ANTLER trial also permits additional backfill patients to be treated concurrently at dose levels that have been deemed safe and well tolerated.

ANTLER Phase 1 Trial Clinical Data for CB-010 at Dose Level 1

The first clinical data from CB-010 at dose level 1 (40x10 6 CAR-T cells) were presented in a poster at the European Hematology Association (“EHA”) Congress in June 2022.

Six patients who received a single infusion of CB-010 at dose level 1 were followed for safety and response, with efficacy based on Lugano criteria and measured by investigator

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assessment and central read.

The most recent data cutoff was as of November 30, 2022, and the following initial responses were observed at dose level 1:

• Six of six patients achieved a complete response (CR) as best response

• Three of six patients maintained a CR at six months

• Two of six patients maintain a CR at 12 months and remain on the trial

• 18 months is the longest CR maintained to date in ANTLER, as achieved by one patient

complete response;

follicular lymphoma;

mantle cell lymphoma;

diffuse large B cell lymphoma;

primary mediastinal large B cell lymphoma

1 Aggressively behaving, with POD24 (high risk)

2 Patient 5’s three-month scan conducted on day 63 post CB-010 as per investigator’s discretion

Results from our ANTLER phase 1 clinical trial showed that six patients at dose level 1 (40x10 6 CAR-T cells) achieved a complete response as best response, with three patients maintaining a CR at six months and two patients maintaining a CR at 12 months.

( ANTLER trial cohort 1 clinical data as of November 30, 2022, data collection ongoing, efficacy based on Lugano criteria .)

Safety results from patients at dose level 1 showed CB-010 was generally well-tolerated with adverse events (“AEs”) as expected for anti-CD19 CAR-T cell therapies.

There were no cases of GvHD.

Grade 3 or 4 treatment emergent adverse events (“TEAEs”) developed in five of six patients.

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.

Two patients experienced Grade 1 CRS (33%) and one patient experienced Grade 3 ICANS (17%), which was characterized as a DLT, for which the patient

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received tocilizumab and steroids and recovered within 39 hours.

This patient went on to achieve a complete response to CB-010 treatment.

1 TEAE in at least 2 patients of any grade or TEAE in at least 1 patient of Grade ≥ 3 are included

2 Related TEAEs include TEAEs with relationship to CB-010 of “probably related” or “related” as evaluated by investigator

Data presented at European Hematology Association (EHA) Congress, June 10, 2022.

Data as of May 13, 2022 data cutoff date

Results from our 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.

Based on promising initial safety and efficacy data at dose level 1, we began enrolling patients at dose level 2 (80x10 6 CAR-T cells).

The data at dose level 2 demonstrated an encouraging safety profile for CB-010 with no DLTs in the three patients treated, enabling enrollment of patients at dose level 3 (120x10 6 CAR-T cells).

We continue to enroll patients at dose level 3 and plan to provide an update from our ongoing ANTLER trial in the second half of 2023.

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.

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 first-in-human, 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

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CARs we evaluated.

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.

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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.

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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:

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

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 T cells to detect and reject the CAR-T cell therapy.

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

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

In 2022, 18% of hematologic malignancies in the United States and 1.8% of all cancers were MM.

In 2023, 1.8% of all cancers were MM.

The median age of diagnosis is 69 years, and there were an estimated 35,730 new cases in 2023 in the United States with an estimated 12,590 deaths in 2023.

Five-year survival in these patients is approximately 58%.

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

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

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

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;

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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 r/r MM.

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

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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, an immunomodulatory drug, and an anti-CD38 antibody, have failed.

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

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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 prior to autologous CAR-T cell therapy.

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 and recommended phase 2 dose (“RP2D”), as shown in figure 16 below.

We are currently recruiting patients at dose level 1 (50x10 6 CAR-T cells).

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 will receive CB-011 at the dose determined in Part A.

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

immunomodulatory drug;

monoclonal antibody;

maximum tolerated dose;

proteasome inhibitor;

recommended Phase 2 dose

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.

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

Part B is an expansion portion where patients will receive CB-011 at the RP2D, determined in Part A.

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.

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

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*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).

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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.

Right panel represents established orthotopic MM tumor xenograft after a single dose CAR-T cell treatment.

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.

Strategy and Rationale

CB-012 is our allogeneic CAR-T cell product candidate that targets CLL-1, a receptor expressed on AML tumor cells.

We make multiple edits to this product candidate using our Cas12a chRDNA technology to enhance its antitumor activity.

We believe CLL-1 is a compelling target for the treatment of AML as it is expressed on >90% of AML tumors and

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leukemic stem cells, but not expressed on HSCs.

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.

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 would not require an HSC transplant to provide them with myeloid compartment cells for sustained immunity.

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.

CB-012 has both checkpoint disruption and immune cloaking armoring strategies.

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:

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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:

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

B2M gene knockout:

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

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Target Indication

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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 AML.

Clinical Development Plan

We are evaluating CB-012 in IND-enabling preclinical studies.

We expect to submit an IND application for CB-012 in the second half of 2023.

Upon clearance of the IND application by the FDA, we plan to evaluate this therapy in patients with r/r AML in a phase 1 clinical trial.

Thus, 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.

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.

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 20 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 a HL-60 CLL-1 expressing AML model in NOD SCID gamma (“NSG”) mice.

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 21 below, the CLL-1-specific CB-012 CAR-T cells statistically significantly increased overall

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survival in the tumor-bearing mice compared to mice that received either control CAR-T cells expressing PD-1 or the vehicle control.

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 and PD-L1-expressing cell line in NSG mice.

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.

Strategy and Rationale

Our CB-020 program is a CAR-NK cell product candidate derived from edited iPSCs designed to target ROR1, an antigen expressed on multiple solid tumors and associated metastases.

Despite their clinical success against hematologic malignancies, CAR-T cells have not yet demonstrated broad, robust antitumor activity in the solid tumor setting.

NK cells are a compelling platform for cell therapy development for targeting multiple different solid tumors.

NK cells are allogeneic and innately target solid tumors and metastases.

We believe edited iPSC-derived CAR-NK cell therapies are a compelling platform for solid tumor-targeting cell therapy development.

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

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.

See figure 22 below.

The iNK cells will include the edits that we believe will be necessary to successfully target the intended solid tumor and overcome the immunosuppressive tumor microenvironment.

There are multiple advantages of using iPSCs.

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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 will then be differentiated into iNK cells and expanded for therapeutic use.

This platform will enable us to generate sophisticated, armored iNK cell product candidates with attributes necessary for targeting solid tumors.

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An outline of the multi-step iPSC to iNK platform we developed to generate CB-020, and potential future product candidates, is shown in figure 22 below.

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.

Target Indication

We have selected ROR1 as the target for our CB-020 product candidate, our first off-the-shelf iPSC-derived CAR-NK cell therapy.

ROR1 may be a promising target for several solid tumor indications.

ROR1 is a cell signaling receptor that is overexpressed on the surface of several solid tumor types and has been shown to drive tumor cell growth, survival, and metastasis.

We have shown that a single dose of iPSC-derived anti-ROR1 CAR-NK cells, administered in a tumor xenograft model, significantly reduced tumor burden compared to iPSC-derived NK cells without an anti-ROR1 CAR.

Preclinical Data

Preclinical data demonstrate that anti-ROR1 CAR-NK cells exhibited increased tumor cell killing in both in vitro and in vivo models.

In figure 23 below, we demonstrated the in vitro cytotoxicity of anti-ROR1 CAR-NK cells.

In this study, iPSC-derived anti-ROR1 CAR-NK cells demonstrated enhanced cell killing compared to iPSC-derived NK cells without a CAR.

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iPSC-derived anti-ROR1 CAR-NK cells demonstrated enhanced cell killing compared to iPSC-derived NK cells without a CAR in an in vitro assay.

In figure 24 below, we demonstrated the in vivo antitumor activity of anti-ROR1 CAR-NK cells.

In this study, a single dose of iPSC-derived anti-ROR1 CAR-NK cells led to statistically significant reduced tumor burden in a solid tumor xenograft model in mice compared to iPSC-derived NK cells without a CAR.

The observation that some antitumor activity occurred with iPSC-derived NK cells without a CAR suggests that an iNK cell product with the ROR1 CAR will target both ROR1+ and ROR1- tumor cells that may exist in solid tumors.

iPSC-derived anti-ROR1 CAR-NK cells led to a reduction of tumor burden in a solid tumor xenograft model in mice compared to iPSC-derived NK cells without a CAR.

CAR-NK Platform Armoring Strategies

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

In figure 25 below, we show that these strategies lead to enhanced antitumor 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 antitumor activity compared to wild -type (“WT”) iNK cells in a solid tumor model, as shown in figure 25 below, left panel.

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.

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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.

Strategic Agreements

We recognize the broad opportunity presented by our genome-editing technologies to benefit patients, and we appreciate that we do not have sufficient resources to fully exploit this potential across multiple indications and applications.

As part of our strategy to maximize the value and benefit of our technologies, we have entered into a strategic collaboration with AbbVie and intend to explore mutually beneficial strategic collaborations with other biotechnology or pharmaceutical companies in the future.

As part of our strategy to maximize the value and benefit of our technologies, we are exploring mutually beneficial strategic collaborations with other biotechnology or pharmaceutical companies.

Additionally, we have in-licensed or taken assignment of key technologies important for the development of our product candidates.

AbbVie Manufacturing Management Unlimited Company

On February 9, 2021, we entered into the AbbVie Agreement.

Pursuant to the AbbVie Agreement, AbbVie selects one target or, for a dual CAR-T product candidate, two targets (each, a “Program Slot”) to develop collaboration CAR-T product candidates (and corresponding licensed products).

For each of AbbVie’s two Program Slots (or up to four Program Slots, if AbbVie elects to expand the number as discussed below), we are collaborating to develop one or more collaboration allogeneic CAR-T products directed toward the single cancer target or target combination chosen by AbbVie and as described in an applicable research plan and budget, utilizing our Cas12a chRDNA genome-editing and CAR-T cell therapy technologies.

We granted AbbVie an exclusive, royalty-bearing, worldwide license, with the right to grant sublicenses, under our Cas12a chRDNA and cell therapy intellectual property, as well as certain genome-editing technology that we may acquire in the future, and intellectual property that may be developed under the collaboration, solely for AbbVie to develop, commercialize, manufacture, and otherwise exploit the collaboration CAR-T product candidates in the field of human diagnostics, prophylactics, and therapeutics.

Under the terms of the AbbVie Agreement, we conduct certain preclinical research, development, and manufacturing activities under the collaboration, including certain activities for the manufacture and supply of licensed product for AbbVie’s phase 1 clinical trials.

AbbVie reimburses us for our activities under the collaboration, including reimbursement for time spent by employees at a designated FTE rate.

The parties have agreed to a 2023 budget to advance the two Program Slots and have also agreed that all CMO manufacturing activities be performed no earlier than 2024.

The duration of the collaboration is not fixed.

We have formed a joint governance committee (“JGC”) to manage the collaboration.

We received $30.0 million in an upfront cash payment and $10.0 million in an equity investment from AbbVie.

During the collaboration, AbbVie may expand from two Program Slots to a total of four Program Slots by paying us an additional $15.0 million for each Program Slot, provided that AbbVie must make the payment within the earlier of (i) 60 calendar days following completion of the phase 1 clinical studies for the initial collaboration CAR-T and (ii) December 31, 2025.

Under the terms of the AbbVie Agreement, we are eligible to receive up to $150.0 million in future developmental, regulatory, and commercialization milestones for each Program Slot and up to $200.0 million in sales-based milestones for each Program Slot.

We are also eligible to receive global royalties on incremental net sales of licensed products sold by AbbVie, its affiliates, and sublicensees in the high-single-digit to low-teens percent range, subject, in certain instances, to various reductions.

AbbVie has selected targets for the two Program Slots and has reserved two additional targets, which may be substituted into the two Program Slots or used for the third or fourth Program Slots if AbbVie expands the number of Program Slots during the collaboration.

We have identified four unavailable targets that AbbVie cannot pursue as long as

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we meet certain criteria.

Additionally, except for AbbVie’s reserved targets and our unavailable targets, if AbbVie wishes to propose a different target, there is a gatekeeper mechanism whereby such target may or may not be available to AbbVie.

The term of the AbbVie Agreement will continue in force and effect until the date of expiration of the last royalty term of the last country in which a licensed product is exploited.

On a licensed product-by-licensed product and country-by-country basis, the royalty term is the period of time beginning on the first commercial sale of a licensed product in a country and ending on the latest of the following three dates:

(i) the expiration, invalidation, revocation, cancellation, or abandonment date of the last Caribou patent that includes a valid claim that claims either (A) the collaboration CAR-T product in the licensed product, or (B) the method of making the collaboration CAR-T product in such licensed product in such country (in the case of (B), only for so long as no biosimilar product is commercially available in such country);

(ii) 10 years from the first commercial sale of such licensed product in such country;

and (iii) the expiration date of regulatory exclusivity for such licensed product in such country.

The AbbVie Agreement may be terminated during the term by either party for an uncured material breach or bankruptcy.

Additionally, AbbVie may terminate the AbbVie Agreement, in its entirety or on a licensed product-by-licensed product basis, effective immediately upon written notice to us, if AbbVie in good faith believes that it is not advisable for AbbVie to continue to exploit the collaboration on CAR-T products or licensed products as a result of a perceived serious safety issue.

AbbVie may also terminate the AbbVie Agreement in its entirety, for any or no reason, upon 90 calendar days’ prior written notice to us.

AbbVie does not have any rights to our CB-010, CB-011, CB-012, or CB-020 product candidates or any other product candidates that we may develop alone or with a third party in the future.

Pfizer Investment

On June 29, 2023, we entered into a Securities Purchase Agreement (“Securities Purchase Agreement”) with Pfizer Inc.

(“Pfizer”), pursuant to which we, in a private placement transaction, sold to Pfizer 4,690,431 shares of our common stock, par value $0.0001 per share, at a purchase price of $5.33 per share, for aggregate gross proceeds of approximately $25.0 million (“Pfizer Investment”).

The issuance and sale of the shares to Pfizer closed on June 30, 2023.

We granted certain registration rights to Pfizer under the Securities Purchase Agreement covering the resale of the shares.

Unless otherwise agreed by Pfizer, we have agreed to use the proceeds from the Pfizer Investment solely in connection with (i) the development program for our allogeneic anti-BCMA CAR-T cell therapy known as CB-011 that is being evaluated in our CaMMouflage clinical trial and/or (ii) any other single-targeted anti-BCMA CAR-T cell therapy using an anti-BCMA single-chain variable fragment owned or controlled by us (collectively, cell therapies described in clauses (i) and (ii) are referred to as a “BCMA Product Candidate”), for 36 months beginning on June 29, 2023.

On June 29, 2023, in connection with the Pfizer Investment, we and Pfizer also entered into an Information Rights Agreement, having a thirty-six (36)-month term.

Under the Information Rights Agreement, we granted Pfizer a 30-calendar day right of first negotiation (“ROFN”) if we commence or engage with any third party with respect to a potential grant of rights to develop and/or commercialize a BCMA Product Candidate, including, without limitation, a license agreement, a co-promotion/co-commercialization agreement, a profit share agreement, a joint venture agreement, or an asset sale agreement (a “Grant of Program Rights”).

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.

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

Through an information sharing committee, we provide calendar quarter updates to Pfizer regarding the development program for a BCMA Product Candidate.

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 (the “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 (“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.

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

The relevant time period commences when the first patient is dosed with our first CLL-1 product candidate in the first phase 1 clinical trial and ends upon the earlier of the third anniversary of approval of our biologics license application (“BLA”) by the FDA or 10 years from the date the first patient was dosed with our first CLL-1 product candidate in the first phase 1 clinical trial.

The relevant time period commences when the first patient is dosed with our first CLL-1 product candidate (CB-012) in the first phase 1 clinical trial and ends upon the earlier of the third anniversary of approval of our biologics license application (“BLA”) by the FDA or 10 years from the date the first patient was dosed with our first CLL-1 product candidate in the first phase 1 clinical trial.

Under the terms of the MSKCC Agreement, the aggregate success payments will not exceed $35.0 million.

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In no event will the combination of success payments and any change of control payment exceed $35.0 million.

The relevant time period during which MSKCC is eligible for success payments and a change of control payment has not yet commenced.

We may terminate the MSKCC Agreement upon 90 calendar days’ prior written notice to MSKCC.

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If MSKCC materially breaches the MSKCC Agreement in certain circumstances (for example, granting a third party a license in our field), then during the time of such uncured material breach, MSKCC will not be entitled to receive any success payments or any change of control payment.

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ProMab Biotechnologies, Inc.

On January 31, 2020, we entered into a Sale and Assignment Agreement with ProMab (as amended, the “ProMab Agreement”) under which we purchased a humanized scFv targeting BCMA and a patent family related thereto for an upfront cash payment of $0.4 million and the potential payments of future royalties to ProMab.

On January 31, 2020, we entered into a Sale and Assignment Agreement with ProMab (as amended, “ProMab Agreement”) under which we purchased a humanized scFv targeting BCMA and a patent family related thereto for an upfront cash payment of $0.4 million and the potential payments of future royalties to ProMab.

To date, five U.S.

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(“Pioneer,” now Corteva Agriscience)

On July 13, 2015, we entered into an Amended and Restated Collaboration and License Agreement (as amended, the “Pioneer Agreement”) with Pioneer (then a DuPont company) that superseded and replaced a prior Collaboration and License Agreement entered into on September 10, 2014.

On July 13, 2015, we entered into an Amended and Restated Collaboration and License Agreement (as amended, “Pioneer Agreement”) with Pioneer (then a DuPont company) that superseded and replaced a prior Collaboration and License Agreement entered into on September 10, 2014.

Under the terms of the Pioneer Agreement, we and Pioneer cross-licensed background CRISPR intellectual property portfolios.

Pioneer granted us an exclusive worldwide license, with the right to sublicense, to its background CRISPR intellectual property in the field of research tools, and a non-exclusive license, with the right to sublicense, for CRISPR in therapeutics and all fields outside of the Pioneer field, including in the field of human and animal therapeutics.

We granted Pioneer an exclusive license, with the right to sublicense, to our background CRISPR intellectual property, including the CVC IP discussed below, in certain agricultural crops, specified microorganisms, a defined industrial bio field, and certain nutrition and health applications (the “Pioneer Exclusive Field”), and a non-exclusive license, with the right to sublicense, to Pioneer for CRISPR in certain defined fields outside of research reagents.

We granted Pioneer an exclusive license, with the right to sublicense, to our background CRISPR intellectual property, including the CVC IP discussed below, in certain agricultural crops, specified microorganisms, a defined industrial bio field, and certain nutrition and health applications (“Pioneer Exclusive Field”), and a non-exclusive license, with the right to sublicense, to Pioneer for CRISPR in certain defined fields outside of research reagents.

The Pioneer Agreement continues until the expiration, abandonment, or invalidation of the last patent or patent application within the licensed intellectual property;

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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.

however, this amendment is applicable to the AbbVie Agreement.

Intellia Therapeutics, Inc.

On July 16, 2014, we entered into a License Agreement (as amended, the “Intellia Agreement”) with Intellia, LLC (now Intellia Therapeutics, Inc.), under which we granted Intellia an exclusive worldwide license, with the right to sublicense, to certain CRISPR-Cas9 technology for a defined field of human therapeutics in exchange for Intellia stock.

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On July 16, 2014, we entered into a License Agreement (as amended, “Intellia Agreement”) with Intellia, LLC (now Intellia Therapeutics, Inc.), under which we granted Intellia an exclusive worldwide license, with the right to sublicense, to certain CRISPR-Cas9 technology for a defined field of human therapeutics in exchange for Intellia stock.

The Intellia Agreement included a license to certain of our future CRISPR-Cas9 intellectual property until such time as our direct or indirect ownership percentage in Intellia dropped below 10%, called the IP cut-off date, which occurred on January 30, 2018.

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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 (the “Leaseback Agreement”), which resolved the arbitration proceeding.

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.

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

On April 16, 2013, we entered into an Exclusive License for Methods and Compositions for RNA-Directed Target DNA Modification and for RNA-Directed Modulation of Transcription with UC and Vienna (as amended, the “UC/Vienna Agreement”), under which we received an exclusive worldwide license, with the right to sublicense, in all fields to the foundational CRISPR-Cas9 patent family co-owned by UC, Vienna, and Dr.

Emmanuelle Charpentier (the “CVC IP”).

On April 16, 2013, we entered into an Exclusive License for Methods and Compositions for RNA-Directed Target DNA Modification and for RNA-Directed Modulation of Transcription with UC and Vienna (as amended, “UC/Vienna Agreement”), under which we received an exclusive worldwide license, with the right to sublicense, in all fields to the foundational CRISPR-Cas9 patent family co-owned by UC, Vienna, and Dr.

Emmanuelle Charpentier (“CVC IP”).

Charpentier has not granted us any rights to the CVC IP, either directly or indirectly.

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We are obligated to reimburse UC for its prosecution and maintenance costs of the CVC IP.

The CVC IP is currently involved in administrative proceedings at the United States 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, ” in Item 1A of this Annual Report on Form 10-K.

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The CVC IP is currently involved in administrative proceedings at the U.S.

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.

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

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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, 2023, we own 59 issued U.S.

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

patents, including nine U.S.

patents covering our Cas9 and Cas12a chRDNA technologies;

257 issued foreign patents;

309 granted foreign patents;

and 90 pending patent applications throughout the world.

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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.

In the United States, patent term may be lengthened by a PTA, which compensates a patentee for administrative delays by the United States Patent and Trademark Office in granting a patent or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.

Additionally, under the Drug Price Competition and Patent Term Restoration Act of 1984 (the “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.

In the United States, patent term may be lengthened by a PTA, which compensates a patentee for administrative delays by the USPTO in granting a patent or may be shortened if a patent is terminally disclaimed over an earlier-filed patent.

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.

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patents are in 2040.

As of March 1, 2023, we own 13 trademark registrations, including five U.S.

trademark registrations, and two pending trademark applications.

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 United Kingdom.

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

trademark registrations, and 8 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.

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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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., Metagenomi Technologies, LLC, and Scribe Therapeutics, Inc.

Companies developing other genome-editing technologies include, among others, bluebird bio, Inc., 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 a superior product to patients due to genome edits we make to improve their persistence with the goal of extending robust CAR-T cell antitumor activity in patients.

Additionally, our pioneering scientific expertise in iPSC-derived NK cells sets the foundation for our first CAR-iNK cell therapy to target an antigen present on multiple solid tumor malignancies.

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 across four major fronts, which include, among others:

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.

• Autologous T cell therapy:

2seventy bio, Inc., Adaptimmune Therapeutics plc, Arcellx.

Inc., Autolus Therapeutics plc, Bristol-Myers Squibb Company, Gracell Biotechnologies Inc., Janssen Biotech, Inc., Kite, a Gilead Company, Legend Biotech Corporation, Lyell Immunopharma, Inc., Novartis International AG, Poseida Therapeutics, Inc., TCR2 Therapeutics Inc., and Vor Biopharma Inc.;

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.;

• In vivo T cell therapy :

Myeloid Therapeutics, Inc.

and Umoja Biopharma;

• Allogeneic T cell therapy:

Allogene Therapeutics, Inc.

Atara Biotherapeutics, Inc., Cellectis S.A., Celyad Oncology SA, CRISPR Therapeutics, Fate Therapeutics, Inc., Gracell Biotechnologies Inc., Kite, Legend Biotech Corporation, Poseida Therapeutics, Inc., Precision BioSciences, Inc., Sana Biotechnology, Inc., and Vor Biopharma 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., Fortress Biotech, Inc., ImmunityBio, Inc., Nkarta, Inc., NKGen Biotech, Inc., and Takeda Pharmaceutical Company Limited;

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 cell therapies:

Other companies are developing CAR-expressing immune cell therapies derived from natural killer T (“NKT”) cells, including Kuur Therapeutics, Inc.;

from macrophages, including Carisma Therapeutics Inc.;

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., GammaDelta Therapeutics Limited, Cytomed Therapeutics Limited, TC Biopharm (Holdings) plc, Hebei Senlang Biotechnology Co.

Ltd., and Beijing Doing Biomedical Technology Co., Ltd.;

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

• 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.

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.

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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 CB-010 and CB-011, 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 ANTLER phase 1 clinical trial and our CaMMouflage phase 1 clinical trial.

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.

We have made a significant investment in process development to facilitate our efforts to improve both the supply chain and our product characterization capabilities.

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 a licensed MaxCyte instrument 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.

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.

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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.

Our process development and manufacturing core competencies and advantages include:

• Standard operating procedures and technologies;

• Process development research from smaller to larger scales;

• Procedures that enable the transfer from process development stage to cGMP conditions;

• Custom engineering to create a robust procedure for each unique pipeline product candidate;

• 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;

• custom engineering and development to create the necessary specific requirements for our product candidates, while leveraging the broader platform to ensure robust processes;

• removal of residual TCR positive T cells after genome editing to minimize the risk of GvHD in patients;

• Evaluation of all manufacturing steps to optimize for maximal productivity and product integrity;

• process understanding and cell manufacturing control for continuous optimization of productivity and product candidate quality;

• closed manufacturing system;

• Focus on efforts to enhance cell viability;

• Enhancement of gene knockout, CAR expression, and gene insertion;

• Improvements in retaining early memory T cell phenotypes;

• Approaches to maximizing the number of doses per batch.

The CMO that is manufacturing the phase 1 clinical supply of our CB-010 and CB-011 product candidates is located in the United States and is subject to cGMP requirements, using both qualified equipment and materials.

We use multiple CMOs to individually manufacture cGMP chRDNA guides, Cas9 and Cas12a proteins, and AAV6 vectors used in the manufacture of our CAR-T and CAR-NK cells.

• highly specific development efforts focused on enhancing cell viability;

• extensive core process knowledge of gene knockout, CAR expression, and gene insertion;

• 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.

Additionally, we may decide to build our own manufacturing facility in the future to provide us greater flexibility and control over our clinical or commercial manufacturing needs.

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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

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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.

Relevant regulatory authorities include, but are not limited to, the FDA, the European Medicines Agency (“EMA”), an agency of the European Union (“EU”) in charge of the evaluation and supervision of medicinal products;

Relevant regulatory authorities include, but are not limited to, the FDA;

the European Medicines Agency (“EMA”), an agency of the European Union (“EU”) in charge of the evaluation and supervision of medicinal products;

the European Commission, which is the executive arm of the EU;

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The processes for obtaining marketing approvals in the United States and in other countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.

In addition, the regulatory framework for the collection, use, safeguarding, sharing, transfer, and other processing of information worldwide is rapidly evolving and is likely to remain uncertain for the foreseeable future.

Licensure and Regulation of Biologics in the United States

In the United States, our product candidates are regulated as biological products, or biologics, under the Public Health Service Act (the “PHSA”), and the Federal Food, Drug, and Cosmetic Act (the “FDCA”), and their implementing regulations promulgated by the FDA.

The failure to comply with the applicable requirements at any time during the product development process, including nonclinical testing, clinical testing, the approval process, or post-approval process, may subject us to delays in the conduct of a clinical trial, regulatory review and approval, and/or subject us to administrative or judicial sanctions.

In the United States, our product candidates are regulated as biological products, or biologics, under the Public Health Service Act (“PHSA”), and the Federal Food, Drug, and Cosmetic Act (“FDCA”), and their implementing regulations promulgated by the FDA.

Failure to comply with the applicable requirements at any time during the product development process, including nonclinical testing, clinical testing, the approval process, or post-approval process, may subject us to delays in the conduct of a clinical trial, regulatory review and approval, and/or subject us to administrative or judicial sanctions.

Such sanctions may include, but are not limited to, the FDA’s refusal to allow us to proceed with clinical testing of our product candidates, refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, receipt of untitled or warning letters, adverse publicity, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, and civil or criminal investigations and penalties brought by the FDA, U.S.

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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 all performed in accordance with the FDA’s current Good Laboratory Practice (“cGLP”) regulations;

• preclinical laboratory tests and formulation studies performed in accordance with the FDA’s current Good Laboratory Practice (“cGLP”) regulations;

• manufacture and testing of clinical investigational product according to cGMPs;

• submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin;

• submission to the FDA of an investigational new drug (“IND”) application for human clinical testing, which must become effective before human clinical trials may begin;

• approval by an independent institutional review board (“IRB”), representing each clinical trial site before each clinical trial may be initiated, or by a central IRB if appropriate;

• performance of adequate and well-controlled human clinical trials 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;

• 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;

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• 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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• payment of user fees and securing FDA approval of the BLA;

• compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy (“REMS”) adverse event reporting, and compliance with any post-approval studies required or requested by the FDA.

• 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

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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 an approved 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.

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.

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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.

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.

In certain cases, we may not be able to proceed at all with our proposed clinical trial.

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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.

When a foreign clinical trial is conducted under a foreign equivalent to an IND application, all FDA IND applications requirements must be met unless waived.

If a non-United States clinical trial is not conducted under a U.S.

FDA IND application, we may submit data from a well-designed and well-conducted clinical trial to the FDA in support of our BLA, so 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.

When a foreign clinical trial is conducted under a foreign equivalent to an IND application, FDA IND applications requirements must be met unless waived.

If a non-U.S.

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.

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Some clinical trials receive additional oversight by an independent group of qualified experts organized by us, known as a data safety monitoring board or committee.

This group receives and reviews data arising from the clinical trial

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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.

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 NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (“NIH Guidelines”).

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.

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”).

Under the NIH Guidelines, recombinant and synthetic nucleic acids are defined as:

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The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial.

Although the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving National Institutes of Health (“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, which was enacted in December 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.

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.

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.

This requirement will become applicable to all clinical trials that begin enrollment 180 days after FDA publishes its final guidance on this topic.

requirement will become applicable to all clinical trials that begin enrollment 180 days after FDA publishes its final guidance on this topic.

Clinical trials typically are conducted in three sequential phases;

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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 trial, in which case a phase 3 clinical trial will not be necessary.

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.

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Other external events may occur that can affect the conduct of our clinical trials, such as pandemics or government shutdowns.

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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.

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The FDA and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols.

For example, the FDA issued a guidance document titled “Human Gene Therapy Products Incorporating Human Genome Editing” in March 2022, providing 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 in an IND application prior to beginning the applicable clinical trial, including information on the design of the gene editing component;

For example, in January 2024, the FDA issued a guidance document titled “Considerations for the Development of Chimeric Antigen Receptor T Cell Products;

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.

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;

delivery mechanisms for the gene editing components;

information on the chemistry, manufacturing, and controls (“CMC”);

information on chemistry, manufacturing, and controls (“CMC”);

risk of unregulated proliferation;

potential implications of off-site gene editing;

among others.

In the same month, the FDA also published a guidance document, titled “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products,” which lays out issues to consider when developing CAR-T products, including establishment of the manufacturing processes, preclinical assessment of the CAR-T cells, and design of the clinical studies, among others.

The FDA also published other guidance documents that relate to gene therapies and will likely continue to do so in the future.

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.

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;

the chemistry, manufacturing, and control information that should be included in an IND application;

the CMC information that should be included in an IND application;

the proper design of tests to measure product potency in support of a BLA application;

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Before approving a BLA, the FDA typically will inspect the facility or facilities where our product candidates are manufactured.

The FDA will not approve a BLA unless it determines that the manufacturing processes and facilities are in full compliance with cGMP requirements and adequate to ensure consistent production of the product within required specifications.

The PHSA emphasizes the importance of manufacturing control for products such as biologics whose

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attributes cannot be precisely defined.

The FDA will not approve a BLA unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to ensure consistent production of the product within required specifications.

The PHSA emphasizes the importance of manufacturing control for products such as biologics whose attributes cannot be precisely defined.

Material changes in manufacturing equipment, location, or process post-approval may result in additional regulatory review and approval.

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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 extensive manufacturing information and detailed information on the composition of the product candidate and proposed labeling as well as payment of a user fee.

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 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.

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.

The FDA does not always meet its PDUFA goal dates for standard and priority BLAs.

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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 our product, it may limit the approved indications for use of our product.

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 the product’s safety after approval.

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

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the benefits of the product outweigh the potential risks.

In addition, the FDA may call for post-approval studies, including phase 4 clinical trials, to further assess a product’s safety after approval.

REMS can include medication guides, communication plans for healthcare professionals, and elements to assure safe use (“ETASU”).

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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.

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.

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.

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.

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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 our product candidates RMAT designations if our 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 our product candidates have the potential to address unmet medical needs for such disease or condition.

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.

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.

Product candidates granted RMAT designation may also be eligible for accelerated approval on the basis of surrogate or intermediate clinical trial endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites, including through expansion to additional sites.

RMAT-designated

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products that receive accelerated approval may, as appropriate, fulfill their post-approval requirements through the submission of clinical evidence, clinical trials, patient registries, or other sources of real-world evidence such as electronic health records, through the collection of larger confirmatory data sets as agreed with the FDA, or via post-approval monitoring of all patients treated with such therapy prior to approval of the therapy.

RMAT-designated products that receive accelerated approval may, as appropriate, fulfill their post-approval requirements through the submission of clinical evidence, clinical trials, patient registries, or other sources of real-world evidence such as electronic health records, through the collection of larger confirmatory data sets as agreed with the FDA, or via post-approval monitoring of all patients treated with such therapy prior to approval of the therapy.

Regenerative medicine advanced therapy designation may be rescinded if our product candidate no longer meets the qualifying criteria.

In 2022, CB-010 was granted RMAT designation for relapsed or refractory LBCL and fast track designation for r/r B-NHL.

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.

clinical benefit.

Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.

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Accordingly, we and our third-party manufacturers must continue to expend time, money, and effort in the areas of production and quality control to maintain compliance with cGMP regulations and other regulatory requirements.

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Our products may also be subject to official lot release, meaning that the manufacturer of our products is required to perform certain tests on each lot of the product before the product is released for distribution.

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Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

In 2022, the FDA granted orphan drug designation to CB-010 for FL.

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The FDA has granted orphan drug designation to CB-010 for the treatment of FL and to CB-011 for the treatment of MM.

Pediatric Studies and Exclusivity

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Biosimilars and Exclusivity

The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (the “Affordable Care Act”) includes a subtitle called the Biologics Price Competition and Innovation Act of 2009 (the “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.

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.

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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

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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 preclinical 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

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 the comparable health regulatory authorities in other countries or jurisdictions before we can initiate clinical trials or marketing of our products in those countries or jurisdictions.

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.

Specifically, the process governing approval of medicinal products in the EU generally follows the same lines as in the United States, although the approval of a medicinal product in the United States is no guarantee of approval of the same product in the EU, either at all or within the same timeframe as approval may be granted in the United States.

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In the United States and other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services often rely on third-party payors to reimburse all or part of the associated healthcare costs.

Patients are unlikely to use any product candidates we may develop unless coverage is provided and reimbursement is adequate to cover a significant portion of the

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cost of such product candidates.

Patients are unlikely to use any product candidates we may develop unless coverage is provided and reimbursement is adequate to cover a significant portion of the cost of such product candidates.

In addition, direct or indirect governmental price regulation may affect the prices that we may charge for product candidates.

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In the United States, no uniform policy of coverage and reimbursement for biological products, including gene and cell therapy products, exists among third-party payors.

As a result, obtaining coverage and reimbursement approval for such a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical, and cost-effectiveness data regarding the products’ clinical benefits, medical necessity, and risks on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained.

As a result, obtaining coverage and reimbursement approval for such a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical, and cost-effectiveness data regarding the product’s clinical benefits, medical necessity, and risks on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained.

A decision by a third-party payor not to cover any product candidates we may develop could reduce physician utilization of such product candidates once approved and have a material adverse effect on our sales, results of operations and financial condition.

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Recently, many European countries have increased the level of discounting required in relation to the pricing of biological products and these efforts could continue as countries attempt to manage healthcare expenditures.

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Healthcare Law and Regulation

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Arrangements with providers, consultants, third-party payors, customers, and patients are subject to broadly applicable fraud and abuse laws including anti-kickback laws, false claims laws, and health care provider payment transparency laws, as well as data privacy and security laws and other healthcare laws that may constrain our business and/or financial arrangements.

Restrictions under applicable federal and state healthcare laws and regulations, include but are not limited to the following:

Violation of these laws may result in significant civil monetary penalties, possible exclusion from participation in U.S.

federal health care programs, and/or criminal penalties.

Restrictions under applicable U.S.

federal and state healthcare laws and regulations, as well as equivalent international laws, include but are not limited to the following:

federal Anti-Kickback Statute (“AKS”), which prohibits, among other things, individuals or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce, or reward, either the referral of an individual, or the purchase, lease, order, arrangement for or recommendation of the purchase, lease, order, arrangement for any good, facility, item, or service, for which payment may be made, in whole or in part, under a federal healthcare program, such as Medicare and Medicaid;

civil and criminal false claims laws, including the civil United States 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 United States False Claims Act;

civil and criminal false claims laws, including the civil U.S.

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.

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;

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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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Numerous federal and state laws and regulations, including federal health information privacy laws, state data breach notification laws, state health information privacy laws and federal and state consumer protection laws (e.g., Section 5 of the Federal Trade Commission Act), that govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our collaborators and third-party providers.

California has enacted the California Consumer Privacy Act (the “CCPA”).

In December 2023, HHS finalized its Health Data, Technology and Interoperability rule, establishing new standards for transparency, information exchange, and interoperability for health information technology.

California has enacted the California Consumer Privacy Act (“CCPA”).

The CCPA gives California residents expanded rights to access and delete their personal information, opt out of certain personal information sharing and receive detailed information about how their personal information is used.

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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.” 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.

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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 United States healthcare industry and elsewhere is cost containment.

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 United States Congress enacted the Affordable Care Act, which, among other things, included changes to the coverage and payment for products under government health care programs.

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;

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;

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• 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

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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.

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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.

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As of March 1, 2024, we have 158 employees.

Of these employees, 77% are primarily engaged in research and development activities and 53% of our research and development personnel have one or more advanced degrees.

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 and regulatory experts, and company builders as part of a passionate team of employees.

Our team includes experts in genome-editing technologies, cellular engineering, computational biology, genome sequencing and analysis, structural biology, chemistry, lab automation, translational medicine, process development, analytical development, medical affairs, clinical operations and development, regulatory affairs, and quality assurance.

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.

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We recognize that attracting, motivating, and retaining talent at all levels is vital to our continued success.

Our employees are a significant asset and we aim to create an equitable, inclusive, and empowering environment in which our employees can grow and advance their careers, with the overall goal of developing, expanding, and retaining our workforce to support our current pipeline and future business goals, while protecting the long-term interests of our stockholders.

Our success depends on our ability to attract, engage, and retain a diverse group of employees.

We value innovation, passion, data-driven decision making, persistence, and honesty, and we are building an inclusive environment where our employees can thrive and be inspired to make exceptional contributions to bring therapies to patients.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, motivating, and integrating our existing and future employees.

The principal purposes of our equity and cash incentive plans are to attract, retain, and motivate 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 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 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, motivate, and retain employees.

Since the start of the COVID-19 pandemic, we have been and will continue to be focused on the safety of our employees.

In response to the COVID-19 pandemic, we have instituted on-site protocols and procedures in accordance with regulations and guidelines promulgated by the Centers for Disease Control, the State of California, the California Department of Public Health, the California Occupational Health and Safety Administration, the County of Alameda, and the City of Berkeley.

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

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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 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.

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Management has committed time and resources for this ongoing initiative.

Additionally, we have a newly established process for the creation of employee resource groups (“ERGs”), which will allow our employees to connect in ways that are meaningful to their individual needs and which will provide a platform for obtaining resources and support at our company.

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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.

Involvement in Our Community

Our headquarters are located in Berkeley, California, and many of our employees are alumni of local universities and some have grown up in the San Francisco Bay Area and attended local schools.

Our headquarters are located in Berkeley, California, and many of our employees are alumni of local universities.

Our employees are talented and passionate people who are committed to making a difference in our community and beyond.

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We at Caribou refer to ourselves as “the herd.” We encourage and value social interactions among the herd.

We hold quarterly events, including participating in Light the Night sponsored by the Leukemia & Lymphoma Society, making “Beads to Beat Cancer” bracelets for the Berkeley Women’s Cancer Resource Center and Make-A-Wish Foundation, as well as a participating in a San Francisco Bay clean-up.

Weather permitting, we also sponsor a monthly “fun run” for employees to either run or walk to the shoreline or in the Berkeley hills.

For several years, we have offered yoga for our employees in Berkeley, and we have continued this in a hybrid in-person/virtual format for all our employees regardless of location.

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.

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 (the “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 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.

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), are available on our website free of charge as soon as reasonably practicable after we electronically file the material with, or furnish it to, the SEC.

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act, are available on our website free of charge as soon as reasonably practicable after we electronically file the material with, or furnish it to, the SEC.

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