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Item 1. Business

2025-03-17 compared with 2024-02-29 · 766 added, 710 removed, 1359 unchanged (52% of the section changed)

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The burden of diseases that can be addressed at their root cause through engineered cells is significant.

We view engineered cells as having the potential to be as therapeutically disruptive as biologic drugs to clinical practice.

Key to making this vision a reality will be finding consistent and scalable means of manufacturing cell-based medicines, and we have invested significantly in our hypoimmune (HIP) platform technology, which we refer to as our HIP platform, with the twin goals of using allogeneic cells that evade immune detection in patients and that we can manufacture at scale.

We are developing cell engineering programs to revolutionize treatment across a broad array of therapeutic areas with unmet treatment needs, including oncology, diabetes, B-cell-mediated autoimmune, and central nervous system (CNS) disorders, among others.

We currently have four clinical trials that are ongoing, or that we expect to commence in the near-term, evaluating our product candidates, or product candidates developed using our technologies, across seven diseases in multiple therapeutic areas, including B-cell malignancies, B-cell-mediated autoimmune disease, and type 1 diabetes (T1D), as described below.

• ARDENT is an ongoing Phase 1 clinical trial evaluating SC291, our hypoimmune-modified CD19 targeted allogeneic chimeric antigen receptor (CAR) T program, in B-cell malignancies, including non-Hodgkin’s lymphoma (NHL) and chronic lymphoblastic leukemia (CLL ) ;

• GLEAM is a Phase 1 clinical trial evaluating SC291 in patients with lupus nephritis (LN), extrarenal lupus (ERL), and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis;

• VIVID is a Phase 1 clinical trial evaluating SC262, our hypoimmune-modified CD22 CAR T program, in patients with relapsed and/or refractory B-cell malignancies who have received prior CD19 CAR T therapy;

• Investigator-sponsored first-in-human study (IST) evaluating UP421, an allogeneic, primary islet cell therapy engineered with our HIP technology, in patients with type 1 diabetes mellitus.

In January 2024, we disclosed initial interim clinical data from the ARDENT trial.

As of January 5, 2024, the cut-off date for our early interim analysis, six patients had been dosed with SC291 and four patients were evaluable (defined as patients dosed with SC291 who had at least one disease assessment), of whom three were dosed with 60M CAR T cells (Dose Level 1) and the other was dosed with 120M CAR T cells (Dose Level 2).

With respect to the four evaluable patients at these two dose levels, we observed no dose limiting toxicities, no SC291-related serious adverse events, and no incidences of graft versus host disease (GvHD).

We also observed no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade or any infections of Grade 3 or higher.

Additionally, we observed at least a partial response in three of the patients, including ongoing complete responses in one patient from Dose Level 1 after three months and the patient from Dose Level 2 after two months.

The SC291 drug product contains CAR T cells that are fully edited hypoimmune cells, which we describe as HIP-edited CAR-T cells, along with partially edited cells, which we describe as non-HIP CAR T cells.

In vitro testing showed evidence that blood and immune cells from each of the four evaluable patients had mounted an immune response to the non-HIP CAR T cells but not to the HIP-edited CAR T cells.

Specifically, HIP-edited CAR T cells from the drug product were not rejected by the innate immune response mediated by the patient’s natural killer (NK) cells, nor did the patients have T cell or antibody responses that recognized these cells.

In contrast, we observed immune responses against the non-HIP CAR T cells in the drug product.

Importantly, this evidence suggests that the patients had an intact immune system capable of recognizing allogeneic cells and that the HIP CAR T cells were able to evade these responses.

These results were consistent across all four evaluable patients and provide early support for the idea that the immune evasion profile of our HIP gene edits in multiple pre-clinical models may translate into human subjects.

We believe this observation supports further dose escalation and dose expansion in the ARDENT trial and broader application of our HIP technology in allogeneic cell therapies in other indications.

We are continuing to enroll and dose patients in the ARDENT trial and expect to share additional data in 2024.

We seek to overcome several existing limitations of gene and cell therapy through our ex vivo and in vivo cell engineering platforms, both of which may facilitate the development of therapies that can transform the lives of patients by repairing cells in the body when possible and replacing them when needed.

For ex vivo therapies, when diseased cells are damaged or missing entirely and an effective therapy needs to replace the entire cell, a successful therapeutic requires large-scale manufacturing of cells that engraft, function, and persist in the body.

Of these, we view cell persistence as the greatest current limitation to dramatically expanding the impact of this class of therapeutics, and in particular, overcoming the barrier of immune rejection of transplanted allogeneic cells.

We believe that product candidates developed with our ex vivo cell engineering platform, which uses hypoimmune-modified allogeneic cells that can “hide” from the patient’s immune system, can address this fundamental limitation and unlock a wave of disruptive therapeutics.

We view engineered cells as having the potential to be as therapeutically disruptive as biologic drugs to clinical practice, enabling us to repair cells in the body when possible and replace them when needed.

We are developing ex vivo and in vivo cell engineering platforms to revolutionize treatment across a broad array of therapeutic areas with unmet treatment needs, including type 1 diabetes, B cell mediated autoimmune diseases, and oncology.

For our ex vivo platform, we have made focused investments in our hypoimmune platform technology, which we refer to as our HIP technology, with the twin goals of engineering allogeneic cells that can "hide" from the patient's immune system to overcome the fundamental challenge of immune rejection and cell persistence, and that we can manufacture at scale.

A successful therapeutic requires cells that can engraft, function, and persist in the body, and we believe our approach can unlock a wave of disruptive therapeutics.

For in vivo therapies that aim to repair and control genes in the body, a successful product candidate requires both gene modification and in vivo delivery of the therapeutic payload.

Of these, we view effective in vivo delivery as the greatest current limitation to dramatically expanding the impact of this class of therapeutics.

To this end, our initial focus is on cell-specific delivery of genetic payloads.

Based upon early clinical as well as extensive preclinical data from our HIP platform, we announced in October 2023 our decision to increase our focus on our ex vivo cell therapy product candidates.

We expect to focus a meaningful portion of our research and development resources and activities for at least the next several years on advancing HIP-modified ex vivo manufactured cells as therapeutics.

To this end, our initial focus is on cell-specific delivery of genetic payloads that integrate into the genome of the target cells.

We currently focus our efforts across three areas and have three ongoing clinical trials across multiple disease types and therapeutic areas, including type 1 diabetes (T1D), B cell mediated autoimmune diseases, and B cell malignancies.

• Type 1 Diabetes :

Approximately nine million people suffer from type 1 diabetes (T1D) worldwide, and there have been no major novel medicines for the disease since insulin.

We are developing SC451, a HIP-modified, stem cell derived pancreatic islet cell therapy, for the treatment of T1D.

The goal of this therapy is euglycemia, or normal blood glucose, without the need for exogenous insulin injections or immunosuppression.

We currently have an ongoing investigator-sponsored first-in-human study (IST) evaluating UP421, an allogeneic, primary islet cell therapy engineered with our HIP technology, in patients with T1D.

Sana expects to share additional data in 2025 and file an investigational new drug application (IND) for SC451 as early as 2026.

• Allogeneic CAR T cells :

We are developing SC291, our HIP-modified allogeneic CD19-dirtected allogeneic CAR T cell product candidate, in patients with B cell mediated autoimmune diseases.

The GLEAM study is a Phase 1 clinical trial evaluating SC291 in patients with lupus nephritis (LN), extrarenal lupus (ERL), and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

If successful, SC291 has the potential to benefit patients in a number of additional B cell-mediated autoimmune diseases.

We are also studying SC262, our HIP-modified allogeneic CD22-directed CAR T cell product candidate.

The VIVID study is a Phase 1 clinical trial evaluating SC262 in patients with relapsed and/or refractory (R/R) B cell malignancies who have received prior CD19-directed CAR T therapy.

Sana is enrolling patients in both the GLEAM and VIVID trials and expects to share data from each study in 2025.

• In vivo CAR T cells :

We are developing SG299, a CD8-targeted fusosome that leverages our fusogen platform technology.

This platform enables cell-specific, in vivo delivery of various payloads, allowing SG299 to deliver genetic material to CD8+ T cells that directs them to become CD19-targeting CAR T cells, while avoiding delivery to potentially problematic tissues such as the liver and gonads.

Sana plans to develop SG299 in a range of B cell cancers and B cell mediated autoimmune diseases and expects to file an IND for SG299 as early as 2026.

In December 2024, UP421, a HIP-modified allogeneic primary islet cell product, was transplanted into a patient with T1D in the IST, which is being conducted at Uppsala University Hospital.

This Phase 1 study evaluates the safety of UP421 when transplanted intramuscularly into a patient with T1D.

Secondary endpoints include immune evasion measured in peripheral blood, non-fasting C-peptide concentrations (which is a measure of the body’s insulin production) in peripheral blood, C-peptide response to a mixed meal tolerance test (MMTT), and graft survival assessed by magnetic resonance imaging (MRI).

The transplantation was performed without immunosuppression, steroids, or any supportive medication to facilitate allogeneic cell survival.

As a first-in-human study, the primary endpoint was safety and the dose was approximately 2% to 7% of islet cells that would typically be needed for insulin independence.

In January 2025, we announced positive results from the IST at four weeks after cell transplantation, which demonstrated the survival and function of pancreatic beta cells as measured by the presence of circulating C-peptide, a biomarker indicating that transplanted beta cells are producing insulin.

Positive preliminary twelve-week clinical results, building on the four-week results, demonstrate that all primary and secondary endpoints were met.

The 42-year-old recipient, who had been living with T1D for over 30 years, received a single transplant of UP421 into the muscle of the forearm.

The primary endpoint of safety was achieved with no drug product-related adverse events reported.

Prior to transplant, C-peptide levels were undetectable both in the non-fasting state and in response to an MMTT.

Pancreatic beta cells produce pro-insulin, which is cleaved and secreted as insulin and C-peptide in a 1:1 ratio, making C-peptide a well-established biomarker of endogenous insulin production.

Results of the study at four- and twelve-weeks after cell transplantation demonstrate the survival and function of pancreatic beta cells as measured by the presence of circulating C-peptide.

C-peptide levels also increase with an MMTT during testing at these timepoints, consistent with insulin secretion in response to a meal.

MRI scanning also demonstrated a sustained signal at the site of transplanted cells over time, which is consistent with graft survival.

No inflammation or safety-related signals were observed.

The UP421 drug product contains a mixture of islet cell populations:

wild-type (WT) islet cells expressing HLA class I and class II, double knockout (DKO) islet cells with HLA class I and class II eliminated, and HIP islet cells with both HLA class I and class II eliminated plus CD47 overexpression.

WT islet cells triggered a robust immune response, with peak T cell activation at day 7 following transplantation, followed by T cell-mediated killing, and development of donor-specific antibodies.

DKO islet cells, while avoiding T cell activation and antibody responses, were rapidly eliminated by natural killer (NK) cells.

In contrast, HIP islet cells demonstrated comprehensive immune evasion, with no evidence of T cell activation, donor-specific antibody development, or NK cell-mediated killing through twelve weeks.

These distinct immune responses were further validated in whole blood assays, in which HIP islet cells uniquely survived exposure to the patient's PBMCs while both WT and DKO islet cells were eliminated.

To our knowledge, this study is the first example of successful transplantation with no immunosuppression into a person with an intact immune system to demonstrate survival and function of allogeneic cells.

We believe these initial results with HIP-modified cells represent a significant milestone for the field of cell therapy.

The results are a key landmark in our effort to develop SC451, our HIP modified stem cell-derived pancreatic islet cell product candidate, as an off-the-shelf cell therapy for patients with T1D.

The 12-week data remain subject to source data verification, after which we and our collaborators at Uppsala University Hospital expect to publish in scientific journals and/or present at scientific conferences more details and longer follow-up from this study in 2025 and beyond.

We expect to submit an IND for SC451 as early as 2026.

GLEAM is a Phase 1 clinical trial evaluating SC291 in patients with LN, ERL, and ANCA-associated vasculitis.

Clinical studies conducted by third parties evaluating B cell depleting agents in B cell mediated autoimmune disease have established that deep B cell depletion is an important correlate of clinical activity, with deeper B cell depletion correlating with better clinical activity for the agents.

We have also studied SC291 in patients with B cell malignancies in a trial we refer to as ARDENT, in which we have seen a tolerable safety profile.

Among sixteen patients, we observed no cases of Grade 2 or higher cytokine release syndrome (CRS), of any Grade immune effector cell-associated neurotoxicity syndrome (ICANS), or of graft versus host disease (GvHD).

We observed a single case of Grade 1 immune effector cell associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS).

All six evaluable non-Hodgkin's lymphoma (NHL) patients treated at the two highest cell dose cohorts showed deep B cell depletion.

We are optimistic that if we observe safe and deep B cell depletion in the GLEAM study similar to that observed in these cohorts of the ARDENT study, then SC291 could have a meaningful clinical benefit for patients in the autoimmune indications being evaluated in GLEAM.

In December 2024, the U.S.

Food and Drug Administration (FDA) granted Fast Track designation for SC291 in relapsed/refractory systemic lupus erythematosus (SLE), which includes LN and ERL.

Fast Track designation is designed to facilitate development and expedite review of drugs that address serious conditions and unmet medical needs.

With respect to our in vivo cell engineering research efforts, in January 2025, we shared data from preclinical studies involving our SG299 CAR T cell fusosome product candidate, a CD8-targeted fusosome that delivers a CD19 CAR to target CD19+ cells.

In a non-human primate (NHP) study exploring the potential efficacy of this therapy, intravenous (IV) injection of a surrogate SG299 together with an additional component resulted in the generation of CAR T cells that induced deep B cell depletion in the peripheral blood and lymph nodes at 28 days.

We believe that deep B cell depletion is an important biomarker for potential efficacy in patients with B cell mediated autoimmune diseases and B cell mediated cancers.

Separately, in a good laboratory practice (GLP) toxicology study in NHPs, we observed that a single IV injection of SG299 demonstrated selective, dose-dependent gene delivery to CD8+ T cells.

Tissue analysis showed minimal to no quantifiable presence in non-target tissues, including the liver and gonadal tissue.

For additional information, see the section titled “T Cell Fusosome Approach” below.

In November 2024, we announced a portfolio prioritization in which we suspended development of SC291 in oncology in the ARDENT study and SC379, our stem-cell derived glial progenitor cell product candidate, in various central nervous system diseases.

Our people are the most important strength of the company.

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• Experienced Company Builders .

We have numerous individuals with vast experience in building disruptive biotech companies.

Our Founder and Chief Executive Officer, Dr.

Steve Harr, was previously CFO of Juno Therapeutics, helping to build the company and its CAR T cell therapy platform until its acquisition.

He is a physician-scientist with experience in basic research, clinical medicine, finance, company building, and operations.

Our Chairman of the Board and co-founder, Mr.

Hans Bishop, is an experienced company builder and operator with success across a number of companies.

• Leading Scientists .

We believe that in order to successfully develop engineered cells as medicines, significant investments in infrastructure and cross-functional capabilities need to be coupled with deep scientific expertise in the cell types of interest within each program.

Our leadership team includes multiple world-class scientists, including researchers who have made seminal discoveries in gene delivery, immunology, CAR T cells, stem cell biology, and gene editing.

We expect to continue to bring in senior world-class scientists to lead our efforts in each therapeutic area we intend to pursue.

Additionally, our research teams have significant experience in various areas of biology.

We have surrounded this team of discovery scientists with drug developers experienced in advancing product candidates through the development process with expertise in areas such as pharmacology, toxicology, regulatory, clinical development, and clinical operations.

We have numerous individuals with vast experience in building disruptive biotech companies, having expertise in basic research, clinical medicine, finance, company building, and operations.

• Leading Scientists and Drug Developers .

We believe that in order to successfully develop engineered cells as medicines, significant investments in infrastructure and cross-functional capabilities need to be coupled with deep scientific and development expertise in the cell types and diseases of interest within each program.

We have assembled a team with deep expertise in transplant immunology, T cell biology, stem cell biology, type 1 diabetes, basic immunology, autoimmunity, drug discovery, and drug development.

• Experienced Manufacturing Scientists, Engineers, and Operators .

Since our founding, we have proactively assembled manufacturing sciences and operations expertise on our board, on our executive team, and across the company.

We have assembled manufacturing sciences and operations expertise on our board, on our executive team, and across the company.

• Board and Investors with Shared Long-Term Vision .

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Our capabilities enable us to take a comprehensive approach to the most important and difficult aspects of engineering cells.

We are primarily pursuing ex vivo cell engineering and can leverage the synergistic proficiencies required to succeed in both approaches.

We are pursuing both ex vivo and in vivo cell engineering platforms and can leverage the synergistic proficiencies required to succeed in both approaches.

We believe we can capitalize on the shared expertise and infrastructure between the platforms to maximize the potential success and the reach of each of our potentially transformative therapies.

We have built deep internal capabilities across a wide range of areas focused on solving the most critical limitations in engineering cells including:

We have built significant internal capabilities across a wide range of areas focused on solving the most critical limitations in engineering cells including:

• Stem Cell and Disease Biology .

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Understanding and harnessing the immune system can have a broad impact across our ex vivo and in vivo cell engineering portfolio.

We are investing in our people and technologies to harness the immune system, particularly T cells, for the treatment of cancer and other diseases.

Additionally, our hypoimmune technology has the potential to “hide” cells from the immune system, unlocking the potential of allogeneic ex vivo therapies for the treatment of numerous diseases.

Our hypoimmune technology, led by a team of transplant immunologists, has the potential to “hide” cells from the immune system, unlocking the potential of allogeneic ex vivo cell therapies for the treatment of numerous diseases We are also investing in our people and technologies to harness the immune system, particularly T cells, for the treatment autoimmune diseases and cancer.

• Genome Modification .

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We are investing in technologies that allow payload delivery to specific cell types and increase the diversity of payloads.

Our Cell Engineering Platforms

Our ex vivo and in vivo Cell Engineering Platforms

The advent of recombinant DNA technology in the 1970s ushered in a new era of therapeutics, enabling the synthetic manufacture of human protein therapies at scale for the first time.

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We believe engineered cells are at a similar inflection point, with key recent technological advancements providing the potential for the broad applicability of this therapeutic class.

Ex vivo Cell Engineering

Engineering cells ex vivo requires the ability to engineer and manufacture cells at scale and then deliver them to the patient so that they engraft, function appropriately, and have the necessary persistence in the body.

Our goal for ex vivo cell engineering is to replace or add any cell in the body such that those cells engraft, function, and persist over time, and to manufacture those cells cost-effectively at scale.

Our goal for ex vivo cell engineering is to replace or add cells in the body such that those cells engraft, function, and persist over time, and to manufacture those cells cost-effectively at scale.

Our ex vivo cell engineering platform uses our hypoimmune technology to create cells that can “hide” from the patient’s immune system to enable persistence of allogeneic cells.

We are primarily focused on making therapies using PSCs with our hypoimmune genetic modifications as the starting material, which we then differentiate into a specific cell type, such as a pancreatic islet cell, before treating the patient.

We are focused on making therapies using PSCs with our hypoimmune genetic modifications as the starting material, which we then differentiate into a specific cell type, such as a pancreatic islet cell, before treating the patient.

Additionally, there are cell types for which effective differentiation protocols from a stem cell have not yet been developed, such as T cells.

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We are now applying our ex vivo cell engineering technologies to make cell products for the treatment of multiple diseases.

We anticipate sharing data in 2024 from multiple clinical trials exploring these therapeutics in various diseases.

In vivo Cell Engineering

Engineering cells in vivo requires the development of both an appropriate delivery vector as well as a payload to effectively modify the target cell.

Our goal for in vivo cell engineering is to repair and control the genes of any cell in the body.

The ultimate aim is to achieve the delivery of any payload, to any cell, in a specific and repeatable way.

We believe that progress in any of these categories can allow us to make important medicines.

Our in vivo cell engineering platform harnesses fusogen technology, which targets cell surface receptors, enabling cell-specific delivery for a meaningful number of different cell types.

We have shown in preclinical studies that our fusogen technology can specifically target numerous cell surface receptors that, when combined with delivery vehicles to form fusosomes, allow cell-specific delivery across multiple different cell types.

Our Portfolio Strategy

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• prioritize efforts where success in one area begets success in others.

We are developing a broad pipeline of clinical product candidates focused on creating transformative ex vivo therapies across a range of therapeutic areas.

We are developing a broad pipeline of clinical product candidates focused on creating transformative ex vivo and in vivo therapies across a range of therapeutic areas.

We are in the early stages of development across a broad pipeline of product candidates, which are summarized below:

Each of our initial programs provides the potential for meaningful standalone value while also supporting our potential ability to further exploit our platforms in a manner that leads to the development of broadly applicable medicines.

1 Investigator sponsored trial.

Abbreviations:

AAV, ANCA-associated vasculitis;

NHL, non-Hodgkin’s lymphoma;

SLE, systemic lupus erythematosus;

T1D, type 1 diabetes;

WW, worldwide.

Each of our programs provides the potential for meaningful standalone value while also supporting our potential ability to further exploit our platforms in a manner that leads to the development of broadly applicable medicines.

PSC-derived Pancreatic Islet Cells

SC451 is our PSC-derived hypoimmune pancreatic islet cell product candidate for the treatment of diabetes, with an initial focus on T1D.

More than nine million patients worldwide have T1D, a disease in which a patient’s immune system attacks and kills pancreatic beta cells, leading to complete loss of insulin production in affected individuals.

These patients represent a small fraction of the overall global diabetes population, which is estimated to be approximately 540 million.

T1D patients typically need to take multiple insulin injections every day for life.

Although the introduction of insulin has had a profoundly positive impact on patients and there has been significant improvement in convenience for patients over the past several decades with the introduction of insulin pumps and continuous glucose monitors, people with T1D have approximately 15 years shorter life expectancies than people without diabetes and are consistently at risk for complications such as coma, stroke, myocardial infarction, kidney failure, and blindness from poorly-controlled blood glucose.

We have shown that we can develop high quality stem cell-derived islet cells that, when transplanted in animal models, normalize blood glucose and cure diabetes.

We have also shown that our hypoimmune cells induce no systemic immune response, survive, and function in a patient with T1D.

We are combining these capabilities and learnings into SC451, and we plan to submit an IND as early as 2026.

These human data are supported by preclinical data in several models, including in NHPs with a pre-existing immune response to non-hypoimmune cells and in a diabetic NHP, where allogeneic, HIP-modified NHP pancreatic islet cells survive and function for the duration of our NHP studies, the longest of which is about forty weeks.

To demonstrate applicability in the context of the autoimmunity seen in people with T1D, we have developed a proprietary mouse model in-house with human immune cells from a T1D patient.

In this model, we showed that HIP modifications enabled stem cell-derived pancreatic islet cells derived from a patient with T1D to evade both the autoimmune and allogeneic immune response, survive, and function for the duration of the study.

T1D is a disease of missing pancreatic beta cells.

Previous results from others have shown that either primary or PSC-derived pancreatic islets, which given with significant immunosuppression, can allow patients to control blood glucose without the need for insulin therapy.

Our human clinical data and our preclinical HIP data support that our HIP-modified pancreatic islets can evade immune detection and potentially eliminate immunosuppression for patients treated with HIP-modified, PSC-derived pancreatic islets.

We believe our HIP-modified, PSC-derived pancreatic islets have the potential to create a disruptive treatment for T1D, offering patients life-long normal blood glucose without immunosuppression.

HIP Primary Islet Cells

UP421 is a HIP-modified allogeneic primary islet cell product that was first transplanted, with no concomitant immunosuppression, into a patient with T1D in December 2024 in an IST being conducted at Uppsala University Hospital.

This Phase 1 trial has a primary endpoint of safety and also evaluates secondary endpoints, including survival and function of the islet cells.

The safety data, secondary endpoints, dosing rationale, clinical outcomes, and immune analysis from the first treated patient are summarized above under the section titled “Overview.” The study is ongoing and continues to evaluate safety, persistence, and function of the transplanted cells.

Allogeneic T Cell Platform

We are first applying our hypoimmune technology to donor derived T cells to be used as allogeneic cell therapies for hematologic malignancies.

We are applying our hypoimmune technology to donor-derived T cells to develop allogeneic cell therapies for B cell mediated autoimmune diseases and B cell malignancies.

These programs are designed to address a major limitation of existing allogeneic CAR T cell therapies:

the need to evade host versus graft responses (HvGR) that occur when a patient’s immune system kills the transplanted T cells, limiting the potential benefit of the therapy.

The rapid killing of the transplanted cell may be a major contributor to the short-lived responses seen in patients treated with allogeneic CAR Ts.

The rapid killing of the transplanted cells may be a major contributor to the short-lived responses seen in patients treated with allogeneic CAR T cells.

One approach to avoid HvGR has been to effectively eliminate a patient’s immune system for a short period using chemotherapy, which puts the patient at risk for severe infections.

Further, the patient’s suppressed immune system inevitably recovers and eliminates the CAR T cells, limiting the effectiveness of the therapy.

Our hypoimmune technology is designed to enable cells to “hide” from the patient’s immune system, giving our allogeneic CAR T cell program the potential to create medicines that persist longer in patients and avoid the risks associated with higher doses of chemotherapy.

Our most advanced hypoimmune product candidate is SC291, a CD19 allogeneic CAR T program that we are evaluating as a potential treatment for NHL and CLL in the ARDENT trial.

Results of our early interim analysis of clinical safety and other clinical responses as well as immune responses to SC291 are discussed above under “Overview” and below under “Allogeneic T Cell Platform — SC291.”

In November 2023, the FDA cleared our Investigational New Drug application (IND) to evaluate SC291 in patients with LN, ERL, and ANCA-associated vasculitis, which we refer to as our GLEAM trial.

Our hypoimmune technology is designed to enable cells to “hide” from the patient’s immune system, giving our allogeneic CAR T cell platform the potential to create medicines that persist longer in patients and avoid the risks associated with higher doses of chemotherapy.

SC291 is being evaluated in patients with LN, ERL, and ANCA-associated vasculitis in a Phase 1 dose escalation study that we refer to as our GLEAM trial.

Patients are currently being enrolled and dosed in this study and we expect to share data in 2025.

B cell depleting therapies, such as anti-CD20 antibodies (e.g., rituximab), have shown clinical benefit in the treatment of multiple autoimmune disorders that involve production of autoimmune antibodies, including LN, ERL, ANCA-associated vasculitis, and many others.

The rituximab trials in systemic lupus erythematosus (SLE) afforded the key insight that the depth of B-cell depletion was associated with improved patient responses.

While these antibodies are adept at depleting B-cells in circulation for many patients, they are unable to penetrate deeply into the germinal centers of the lymph node and tissues, where the pathogenic B-cells continue to survive and drive disease.

CD19 CAR T cells are known to cause deep B-cell depletion in CAR T recipients.

Georg Schett and his research group in Erlangen, Germany tested the treatment of refractory SLE patients with autologous CD19 CAR T cells and were successful in inducing long-lasting drug-free remissions for these patients in the study.

In our ongoing ARDENT trial, we have observed the pharmacodynamic effect of peripheral blood B-cell depletion, which refers to diminishing B-cell counts in the peripheral blood, associated with SC291 treatment in patients.

While pharmacodynamic effects seen in oncology patients may not translate to patients with autoimmune disease, we believe these data increase the probability that SC291 treatment confers similar B-cell depletion, the putative mechanism of benefit, to patients with B-cell-mediated autoimmune disorder.

SC291 also provides the benefit of being available “off the shelf,” avoiding the complex management of patients around the apheresis procedure for cell harvest and between cell harvest and infusion required for treatment with autologous CAR T products while also providing the potential for increased manufacturing scalability.

We expect to share data from the GLEAM trial in 2024.

Initial clinical success with SC291 would support the expansion of our allogeneic CAR T efforts with additional product candidates targeting other patient populations.

Our allogeneic T cell platform is designed to enable the substitution of CAR constructs in a modular fashion.

For the near-term, we are prioritizing clinically-validated targets as well as CAR constructs, such as our CD19 CAR, that have shown promising safety and efficacy profiles in hematologic malignancies in the autologous context.

We are developing SC262, our hypoimmune-modified CD22-directed allogeneic CAR T program, initially as a potential treatment for patients with relapsed and/or refractory B-cell malignancies who have received prior CD19-directed CAR T therapy in NHL, CLL, and acute lymphocytic leukemia (ALL).

In January 2024, the FDA cleared our IND to evaluate SC262 in this patient population.

We refer to the Phase I clinical study as our VIVID trial.

The CD22 CAR construct that we use in SC262, which we licensed from the National Institutes of Health, has already been evaluated in multiple academic clinical trials of autologous CAR T cell therapies, data from which have shown complete responses (CR) in a substantial number of patients that have relapsed following treatment with a CD19-directed CAR T therapy.

Data from a Phase 1 trial (n=38) of NHL patients conducted at Stanford University, where 97% of patients were either refractory and/or relapsed after prior CD19 CAR T therapy, demonstrate a CR rate of 53% and an overall response rate (ORR) of 68%.

The rituximab trials in SLE afforded the key insight that the depth of B cell depletion was associated with improved patient responses.

Although these antibodies are adept at depleting B cells in circulation for many patients, they are unable to penetrate deeply into the germinal centers of the lymph node and tissues, where the pathogenic B cells continue to survive and drive disease.

CD19-directed CAR T cells are known to cause deep B cell depletion in CAR T therapy recipients.

Georg Schett and his research group in Erlangen, Germany tested the treatment of refractory SLE patients with autologous CD19-directed CAR T cells and were successful in inducing long-lasting drug-free remissions for these patients.

In our ARDENT trial, we observed the pharmacodynamic effect of peripheral blood B cell depletion, which refers to diminishing B cell counts in the peripheral blood, associated with SC291 treatment in patients.

Although pharmacodynamic effects seen in oncology patients may not translate to patients with autoimmune disease, we believe these data increase the probability that SC291 treatment will confer similar B cell depletion, the putative mechanism of benefit, to patients with B cell mediated autoimmune diseases.

SC291 also provides the benefit of being available “off the shelf,” avoiding the complex management of patients with respect to the apheresis procedure for cell harvest and between cell harvest and infusion required for treatment with autologous CAR T products, while also providing the potential for increased manufacturing scalability.

We are developing SC262, our hypoimmune-modified CD22-directed allogeneic CAR T program, initially as a potential treatment for patients with relapsed and/or refractory B cell malignancies who have received prior CD19-directed CAR T therapy in NHL.

In January 2024, the FDA cleared our IND to evaluate SC262 in this patient population in a Phase 1 clinical study that we refer to as our VIVID trial.

We are enrolling patients in this trial and expect to share data in 2025.

The CD22-directed CAR construct that we use in SC262, which we licensed from the National Institutes of Health, has already been evaluated in multiple academic clinical trials of autologous CAR T cell therapies, data from which have shown complete responses (CR) in a substantial number of patients that have relapsed following treatment with a CD19-directed CAR T therapy.

For example, data from a Phase 1 trial (n=38) of NHL patients conducted at Stanford University, where 97% of patients were either refractory and/or relapsed after prior CD19-directed CAR T therapy, demonstrated a CR rate of 53% and an overall response rate (ORR) of 68%.

Seventy-five percent of the CRs lasted 12 months or longer.

Modular Pipeline for Allogeneic CAR T Therapy

Allogeneic CAR T development candidates are manufactured from T cells purified from donor PBMCs.

T cells undergo genome modification to disrupt MHC class I and class II expression (which inactivates adaptive immune responses), disrupt TCR expression (which minimizes graft vs.

host disease) and overexpress CD47 (which enables cells to evade the innate immune system, including macrophages and NK cells).

Development candidates principally differ in the CAR expressed by the cells.

Expansion during manufacturing allows production of hundreds of patient doses per donor (based on current scale and accounting for hold back necessary for testing and dose variability).

We are developing SC255, a B-cell maturation antigen (BCMA)-directed allogeneic CAR T, for the treatment of multiple myeloma (MM).

The BCMA CAR construct that we use in SC255, which we licensed from IASO Biotherapeutics and Innovent Biologics is part of equecabtagene autoleucel (Fucaso;

China’s National Medical Products Administration has approved the new drug application for this drug in adult patients with relapsed or refractory multiple myeloma who previously received 3 or more lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).

Data from such trials presented at the American Society of Hematology Annual Meeting in December 2023 showed an overall response rate of 96%, a minimal residual disease (MRD) negativity rate of 94%, and a complete response/stringent complete response (CR/sCR) rate of 78% in 103 patients.

At one year, 81% of patients continue to be MRD negative.

The SC255 program has completed a battery of pre-clinical tests and is currently gated based on resource availability.

In the future, additional candidates may be nominated to address hematological malignancies, solid tumors, and autoimmune disease.

We are developing SC379, our PSC-derived glial progenitor cell (GPC) product candidate, as a therapy to deliver to patients with certain central nervous system disorders healthy allogeneic GPCs, which are the precursors to both astroglia and myelin-producing oligodendrocytes.

SC379 has the potential to treat patients with myelin- and glial-based disorders, which represent a broad group of debilitating neurological disorders, such as multiple sclerosis (MS) and a number of neurodegenerative disorders, none of which have effective treatment alternatives.

We intend to develop SC379 for the treatment of secondary progressive MS, Pelizaeus-Merzbacher disease (PMD), other myelin-based disorders, Huntington’s disease, and other astrocytic diseases.

Our goal is to begin clinical testing for SC379 as early as 2025.

PSC-derived Pancreatic Islet Cells

SC451 is our PSC-derived hypoimmune pancreatic islet product candidate for the treatment of diabetes, with an initial focus on type 1 diabetes mellitus (T1DM).

Greater than 8 million patients worldwide have T1DM.

T1DM is a disease in which a patient’s immune system attacks and kills pancreatic beta cells, leading to complete loss of insulin production in affected individuals.

Patients typically need to take multiple insulin injections every day for life.

Although the introduction of insulin has had a profoundly positive impact on patients, people with T1DM have approximately 15 years shorter life expectancies than people without diabetes and are consistently at risk for complications such as coma, stroke, myocardial infarction, kidney failure, and blindness from poorly controlled blood glucose.

We and our collaborators have shown that we can develop high quality stem cell-derived islet cells that, when transplanted in animal models, normalize blood glucose and cure diabetes.

We have also shown that our hypoimmune cells induce no systemic immune response, even in non-human primates (NHPs) with a pre-existing immune response to non-hypoimmune cells, and that our allogeneic NHP hypoimmune islet cells survive for the duration of our NHP studies, the longest of which is about forty weeks.

To demonstrate applicability in the context of T1DM, we have developed a proprietary mouse model in-house, with humanized immune cells from a T1DM patient, and showed that hypoimmune modifications enabled T1DM patient-derived stem cell islet cells to evade both the autoimmune and allogeneic response.

As a result, we believe our stem cell-derived hypoimmune pancreatic islet cells have the potential to create a disruptive treatment for T1DM, offering patients life-long normal blood glucose without immunosuppression.

We are working on process development and IND-enabling studies.

In November 2023, the Swedish Medical Products Agency authorized Uppsala University Hospital’s clinical trial application (CTA) for an investigator-sponsored, first-in-human study evaluating UP421, an allogeneic, primary islet cell therapy engineered with our hypoimmune technology, in patients with T1DM (the IST).

Human pancreatic islet transplantation from allogeneic donors into T1DM patients has been shown to reduce or even eliminate long-term exogenous insulin dependence, albeit when administered with immunosuppression which leads to toxicity.

Under the IST, a group of experienced pancreatic islet transplantation experts will transplant allogeneic primary islet cells that have been genetically modified with the hypoimmune modifications into T1DM patients without immunosuppression.

We believe that a stem cell-derived islet product candidate such as SC451 would likely maximize the benefit to patients, with superior manufacturing scalability and consistency when compared to primary islet cells.

However, we are optimistic that immunology insights gained from the IST, particularly whether the hypoimmune modifications lead to long-term survival and evasion of either allogeneic or autoimmune killing of the cells, may provide direct insights and learnings applicable to SC451, potentially accelerating development of this product candidate.

We expect data from the IST to be shared in 2024.

Our allogeneic T cell platform is designed to enable the substitution of CAR constructs in a modular fashion.

For the near-term, we are prioritizing clinically validated targets as well as CAR constructs, such as our CD19-targeted CAR, that have shown promising safety and efficacy profiles in the autologous context.

In the future, additional candidates may be nominated to address various diseases, such as autoimmune diseases, hematological malignancies, and solid tumors.

In vivo CD19-Directed CAR T Cells

Our most advanced CAR T cell fusosome product candidate is SG299, a CD8-targeted fusosome that delivers a CD19-directed CAR to target CD19+ cells.

We are developing SG299 to treat patients with hematologic malignancies and B cell mediated autoimmune diseases.

Our in vivo platform provides an opportunity to develop potential product candidates that can expand access to CAR T cell therapy to patients in need.

The effectiveness of ex vivo -manufactured CAR T cells currently depends on the administration of a lymphodepleting preparative regimen prior to infusion to facilitate expansion of the CAR T cell product, which can have an adverse impact on safety.

We do not expect to need a lymphodepleting regimen prior to in vivo delivery of the CAR gene via fusosome, as our goal is to expose our fusosomes to as many T cells in the body as possible.

We also believe the ability to deliver a payload encoding a CAR to a T cell without significant ex vivo manipulation has the potential to be more effective than ex vivo -manufactured CAR T cell products, generating therapeutically active CAR T cells without the complexities and delays associated with the processes of T cell collection and ex vivo manufacturing that are used in currently approved autologous CAR T cell products.

Furthermore, the ex vivo expansion of cells in the presence of high cytokine concentrations, although necessary for the manufacture of currently approved CAR T cell products, also contributes to marked changes in T cell quality that may not be therapeutically beneficial.

The generation of a CAR T cell within the natural physiological environment in vivo has the potential to improve the quality of the CAR T cell generated, potentially improving both efficacy and the side effect profile We anticipate submitting an IND for SG299 as early as 2026.

Our ex vivo Cell Engineering Platform

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• Immunology and genome modification .

We believe that a deep understanding of the immunological response to engineered cells is essential to unlocking the potential of ex vivo therapies.

We have licensed technologies from Harvard University, the University of California San Francisco, Washington University, and others to enable this effort.

In addition, in order to create successful hypoimmune cells, we are investing in building out our gene editing, genome modification, and gene insertion capabilities.

We believe that a deep understanding of the immunological response to allogeneic cells is essential to unlocking the potential of ex vivo cell therapies.

We have invested significantly in transplant immunology to understand the drivers of this immune response and potential cell modifications that will hide cells from allogeneic rejection.

We have also built gene editing, genome modification, and gene insertion capabilities in order to modify the genome of cells so that transplanted, allogeneic cells can evade immune detection.

• Manufacturing .

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We have entered into agreements with contract development and manufacturing organizations (CDMOs) and other partners for access to facilities and reagents in our supply chain necessary to manufacture our product candidates.

We have built a pilot manufacturing plant in South San Francisco, California and entered into a long-term lease agreement for a manufacturing facility in Bothell, Washington, where we intend to build our own clinical trial and commercial current Good Manufacturing Practice (cGMP) manufacturing capabilities.

We entered into a lease agreement under which we have obtained access to manufacturing capabilities within University of Rochester Medical Center’s cell-based manufacturing facility to support manufacturing for early-stage clinical trials.

We are also investing to obtain and ensure access to high quality donor-derived T cells and GMP-grade PSC lines for our programs.

We have built a pilot manufacturing plant in South San Francisco, California and entered into a long-term lease agreement for a manufacturing facility in Bothell, Washington.

We are also investing to obtain and ensure access to high quality donor-derived T cells and current good manufacturing practice (GMP)-grade PSC lines for our programs.

We will continue to invest in our manufacturing capabilities to ensure our pipeline needs are met.

Our Approach to Building our ex vivo Cell Engineering Portfolio

We have prioritized cell types for our programs when:

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• existing proof of concept in humans and/or animal models demonstrates that cell transplantation should have a clinical benefit;

• evidence exists that the cell type can be successfully differentiated from PSC and that such stem cell-derived cells can function appropriately in vivo;

• evidence exists that the cell type can be successfully differentiated from PSCs and that such PSC-derived cells can function appropriately in vivo ;

• there has been the ability to hire or partner with world experts in the field to ensure our programs are rooted in a deep understanding of the underlying cell and disease biology;

• evading immune system rejection via the hypoimmune technology is either not required initially (such as for glial progenitor cells (GPCs)) or is the critical missing element to developing a cell therapy (such as islet cells).

Based on this prioritization, we are focused on three cell types:

T cells, islet cells, and GPCs.

• evading immune system rejection via the hypoimmune technology is either not required initially or is the critical missing element to developing a cell therapy (such as pancreatic islet cells).

Based on this prioritization, we are currently focused on two cell types:

pancreatic islet cells and T cells.

Historical Context of ex vivo Therapy

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These are embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and donor-derived cells.

Our portfolio currently reflects a mix of sources, with the ambition of transitioning primarily to iPSCs over time.

Our portfolio currently includes a mix of sources.

Crucial aspects of developing allogeneic cells from any source include a thorough characterization of the cells, a comprehensive understanding of the global regulatory environment, and an ability to maintain cells under the required conditions, such as GMP, at various stages of the manufacturing processes.

We believe our early investment in building capabilities in the science and manufacturing of these cells will increase our likelihood of success.

This investment is intended to yield sources of cells suitable for the global clinical development and commercialization of ex vivo engineered cells for a broad patient population, in line with our vision to democratize access.

Embryonic Stem Cells

The recognition that every cell in the body originates from a zygote, or fertilized egg, led to the research and ultimate discovery of human ESCs, with the derivation of the first human ESC line in 1998.

ESCs are PSCs which have the potential to differentiate into any cell type and are derived from the inner cell mass of a blastocyst or pre-implantation stage embryo.

ESCs are PSCs that have the potential to differentiate into any cell type and are derived from the inner cell mass of a blastocyst or pre-implantation stage embryo.

They are typically cultured in vitro and grown through cycles of cell division, known as passages, until a line of cells is established that can proliferate without differentiating, and retain their pluripotency while remaining well characterized, including being free of potentially deleterious genetic mutations.

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Although these T cells are neither pluripotent nor from an infinitely renewable source, they can be obtained as mature cells from human donors at scale.

The use of donor-derived cells for our T cell programs should allow us to rapidly advance the programs towards the clinic with the implementation of our hypoimmune technology.

Approach to Sources of Allogeneic Cells

The use of iPSCs as the starting material for our programs offers regulatory and cultural advantages over ESCs, and scale and product consistency advantages over donor-derived allogeneic cells.

Our portfolio currently reflects a mix of sources, which is primarily driven by historical factors as well as current better characterization of genomic stability through differentiation.

Our ambition is to transition primarily to iPSCs over time.

Crucial aspects of developing allogeneic cells from any source include a thorough characterization of the cells, a comprehensive understanding of the global regulatory environment, and an ability to maintain cells under the required conditions, such as cGMP, at various stages of the manufacturing processes.

We believe our early investment in building capabilities in the science and manufacturing of these cells will increase our likelihood of success.

This investment is anticipated to yield sources of cells suitable for the global clinical development and commercialization of ex vivo engineered cells for a broad patient population, in line with our vision to democratize access.

The use of donor-derived cells for our T cell platform may enable us to more rapidly advance product candidates towards the clinic with the implementation of our hypoimmune technology.

Background on Immunological Barriers to ex vivo Therapies and Current Limitations

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Our goal is to create a universal cell capable of evading immune detection, regardless of cell type or transplant location.

Our current clinical hypoimmune technology, which is being used in our SC291, SC262, and SC255 product candidates, combines three genome modifications to “hide” these cells from the host immune system:

Our current clinical hypoimmune technology, which is being used in our SC291 and SC262 product candidates, combines three genome modifications to “hide” these cells from the host immune system:

• disruption of MHC class I expression;

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Once these modifications have been applied to a cell, we refer to that cell as a hypoimmune cell.

Creating Hypoimmune Therapeutic Cells from Human iPSCs

Our current clinical hypoimmune technology combines the following three gene modifications to “hide” cells from the host immune system:

disruption of MHC class I and class II expression (which inactivates adaptive immune responses), and overexpression of CD47 (which “hides” cells from the innate immune system, including macrophages and NK) cells.

PSCs from healthy donors are used as the starting material and are then genetically modified with the hypoimmune modifications.

These edited cells are then differentiated into cell types of therapeutic interest, which could potentially be administered to a patient as an “off the shelf” therapy.

Preclinical Development of Hypoimmune Cells

We and our licensors have carried out a series of experiments in various model systems of increasing immunological complexity.

These included (i) transplanting undifferentiated mouse hypoimmune iPSCs into MHC mismatched allogeneic mice, (ii) transplanting mouse hypoimmune iPSC-derived differentiated cells, such as endothelial cells, into MHC mismatched allogeneic mice, (iii) transplanting human hypoimmune iPSCs into MHC mismatched humanized allogeneic mice, (iv) transplanting NHP hypoimmune iPSCs into MHC mismatched allogeneic NHPs, (v) transplanting NHP hypoimmune iPSC-derived differentiated cells, such as cardiomyocytes, into MHC mismatched allogeneic NHPs, and (vi) transplanting NHP hypoimmune primary cells, such as islets, into MHC mismatched diabetic and non-diabetic NHPs.

Each mouse experiment evaluated:

• whether hypoimmune cells can be successfully transplanted into the recipient without the need for immunosuppression and without eliciting an immune response;

• whether differentiated cells derived from our hypoimmune cells were successfully engrafted in the recipient without needing immunosuppression and without eliciting an immune response.

We have also investigated the NHP immune response to human iPSCs, NHP iPSCs, NHP iPSC-derived differentiated cells, and NHP primary islets.

Importantly, we have shown that hypoimmune primary islets can mediate insulin independence in a fully immunocompetent diabetic NHP without immunosuppression.

This confirms that hypoimmune modifications confer immune evasion without compromising islet function in this setting.

These included (i) transplanting undifferentiated mouse hypoimmune iPSCs into MHC mismatched allogeneic mice, (ii) transplanting mouse hypoimmune iPSC-derived differentiated cells, such as endothelial cells, into MHC mismatched allogeneic mice, (iii) transplanting human hypoimmune iPSCs into MHC mismatched humanized allogeneic mice, (iv) transplanting NHP hypoimmune iPSCs into MHC mismatched allogeneic NHPs, (v) transplanting NHP hypoimmune iPSC-derived differentiated cells, such as cardiomyocytes or retinal pigment epithelial cells (RPEs), into MHC mismatched allogeneic NHPs, and (vi) transplanting NHP hypoimmune primary cells, such as islets, into MHC mismatched diabetic and non-diabetic NHPs.

We have shown that HIP-modified cells survive and evade immune detection in each of these settings.

Importantly, these results include experiments in NHPs, including testing of hypoimmune primary islets.

We have shown that hypoimmune primary islets can mediate insulin independence in a fully immunocompetent diabetic NHP without immunosuppression.

These results confirm that hypoimmune modifications confer immune evasion without compromising islet function in this setting.

We are encouraged by the data from these investigations, given the similarity of the NHP immune system to the human immune system and that NHP models represent the strictest test outside of evaluating these cells in humans.

We are evaluating both iPSCs as well as differentiated cells transplanted into the microenvironments we intend to target in humans.

Based on the results of these NHP studies, we expect to test these hypoimmune cells in humans as a next step.

Mouse iPSC-Derived Hypoimmune Cells Transplanted into MHC Mismatched Allogeneic Mouse

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We also evaluated the ability to successfully engineer human hypoimmune cells from human iPSCs and whether differentiated cells derived from human hypoimmune cells retain biological function.

Creating Hypoimmune Therapeutic Cells from Human iPSCs

Our current clinical hypoimmune technology combines the following three gene modifications to “hide” cells from the host immune system:

PSCs from healthy donors are used as the starting material and are then genetically modified with the hypoimmune modifications.

These edited cells are then differentiated into cell types of therapeutic interest, which could potentially be administered to the patient as “off the shelf” therapies.

First, the three genome modifications described above were replicated in human iPSCs to engineer a human hypoimmune cell line with properties comparable to the mouse hypoimmune cells in vitro .

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It was also observed that the hypoimmune endothelial cells formed primitive vasculature with active blood flow, and the hypoimmune cardiomyocyte cells matured into functional-looking heart cells.

Absence of T and B-Cell Activation Following Transplantation of Hypoimmune Human iPSCs into Mismatched Humanized Mice

T cell activation was measured by EliSpot counts for interferon-gamma production.

Immune cells from mice that received wild type (wt) iPSC grafts show a brisk interferon response when tested against allogeneic wt iPSC grafts.

By contrast, immune cells from mice that received hypoimmune cells (MHC class I/II disruption, CD47 tg) cells show only minimal interferon production when exposed to allogeneic hypoimmune cells, comparable to background frequency in non-immunized mice.

Right panels:

B-cell activation was measured by antibody binding to each cell type, shown as mean fluorescence intensity (MFI).

Wild type cells exhibit significant antibody binding when incubated with serum from mice that received wt cells.

By contrast, hypoimmune cells show only background levels of binding when treated with serum from mice that received hypoimmune cells.

Adapted from Deuse et al, Nature Biotechnology 2019.

CD47 is Required to Protect Hypoimmune Cells from Killing by Human NK Cells

Human iPSCs were differentiated into endothelial cells (hiECs) and plated as a monolayer in a multielectrode system.

After exposure to NK cells, monolayer viability was measured by electrical impedance, indicated here as normalized cell index.

As expected, wt cells were not killed by NK cells.

By contrast, cells lacking MHC class I and II (MHC class I/II disruption), but not expressing CD47, were rapidly killed.

Addition of CD47 tg prevented killing by NK cells.

A blocking antibody to CD47 abolished protection from NK cells, affirming the importance of CD47 overexpression in protection from innate immune cell killing.

From Deuse et al, Nature Biotechnology 2019.

Survival of Hypoimmune Human iPSC Grafts in MHC-Mismatched Humanized Mice

Wild type (wt) and hypoimmune (MHC class I/II disruption and CD47 tg) iPSCs were engineered to express firefly luciferase before transplantation.

Emission of light was used as an index of graft cell viability.

Sequential light emission scans from the same representative animal receiving wt cells show progressive loss of graft viability, indicating graft rejection, confirmed quantitatively in the line tracings below.

By contrast, mice receiving hypoimmune cells show graft expansion over the course of the experiment, indicating immune evasion.

From Deuse et al, Nature Biotechnology 2019.

NHP Hypoimmune Cells Transplanted into NHPs

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No immunosuppression was administered to any of the NHPs in the study.

Allogeneic Hypoimmune iPSCs Survive in vivo in NHPs with an Intact Immune System

Allogeneic Hypoimmune iPSCs Survive in vivo in NHPs with Intact Immune Systems

Unmodified wild type (wt) NHP iPSCs (Group 1, top row) or hypoimmune NHP iPSCs (Group 2, bottom row) were introduced via intramuscular injection into allogeneic NHPs.

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iPSC survival in vivo is followed over time using bioluminescence imaging (BLI).

Data published in Hu et al., Nat Biotechnology 2024 Mar;42(3):413-423.

Absence of T Cell, B Cell, or NK Cell Responses Following the First Delivery and Crossover of Hypoimmune NHP iPSCs into NHPs

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Data above are collected from four NHPs in each experimental arm.

Data published in Hu et al., Nat Biotechnology 2024 Mar;42(3):413-423.

NHP hypoimmune iPSCs grafted into NHPs elicited no detectable systemic immune responses, including no T cell activation and no antibody formation.

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They also suggest that these hypoimmune iPSCs have the potential for immune evasion even the context of a new immune response toward iPSCs without these edits.

In addition, we recently conducted experiments in which we observed immune evasion and cell survival of hypoimmune NHP iPSC-derived cardiomyocytes and retinal pigment epithelial cells (RPEs).

In other experiments, we observed immune evasion and cell survival of hypoimmune NHP iPSC-derived cardiomyocytes and RPEs.

In separate experiments, these cardiomyocytes and RPEs were injected into the hearts and eyes (subretinal space), respectively, of healthy allogeneic NHP recipients without immunosuppression.

Both the hypoimmune cardiomyocytes and RPEs were found to evade systemic adaptive and innate immune responses and survived for the duration of the applicable experiment.

Separately, we have shown that hypoimmune NHP islet cells transplanted into a non-matched allogeneic NHP survive for the duration of the study, which at this point is 40 weeks.

Separately, we have shown that hypoimmune NHP islet cells transplanted into a non-matched allogeneic NHP survive for the duration of the 40-week study,

We conducted an experiment to better understand whether hypoimmune modifications impair the function of islet cells and to confirm that these modifications enable the islet cells to evade immune responses.

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Primary islet cell survival in vivo is followed over time using bioluminescence imaging (BLI).

Data published in Hu et al., Nat Biotechnology 2024 Mar;42(3):413-423.

In January 2024, we presented data from a study transplanting allogeneic HIP-modified pancreatic islet cells into a fully immunocompetent, diabetic NHP.

Subsequent to diabetes being induced in the NHP with streptozotocin, daily insulin injections were performed to re-establish glucose control.

Subsequent to diabetes being induced in the NHP with streptozotocin (STZ), daily insulin injections were performed to re-establish glucose control.

After 78 days, the NHP underwent transplantation of HIP primary islets by intramuscular injection, resulting in insulin independence without the use of any immunosuppression.

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Despite insulin supplementation, widely fluctuating blood glucose levels were observed and no steady state was re-established for the remainder of the study.

Data published in Hu et al., 2024, Cell Stem Cell 31, 334–340.

Hypoimmune Islet Cells Normalize C-peptide Levels after Allogeneic Transplantation in a Fully Immunocompetent NHP

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Destruction of HIP islet cells by anti-CD47 antibody coincides with the decline in C-peptide levels in the serum, confirming that HIP islet cells were required for continued production of C-peptide in the NHP.

Data published in Hu et al., 2024, Cell Stem Cell 31, 334–340.

Based on our preclinical data to date, we believe our hypoimmune technology has the potential to address the most fundamental limitation of ex vivo therapies, persistence, and thereby unlock waves of potentially disruptive therapies across a variety of cell types.

The preliminary clinical findings from the first-in-human transplantation of UP421, our HIP-modified allogeneic primary islet cell product, in the IST being conducted at Uppsala University Hospital further validate our preclinical observations.

These initial human data demonstrate that HIP-modified islet cells can survive and function without immunosuppression.

The detection of C-peptide production and comprehensive immune evasion in the IST represents a significant step toward addressing the fundamental challenge of cellular persistence in transplantation therapies.

The preliminary results from the IST are described in greater detail below in the section titled “Pancreatic Islet Cell Program.”

Safety Switch for Hypoimmune Cells

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We believe these data support use of anti-CD47 antibodies as a potential safety strategy.

We have identified several additional safety switches with in vivo activity and intend to continue to explore them and potentially include multiple safety switches in our therapeutic programs moving forward.

We have identified several additional safety switches with both in vitro and in vivo activity and will include one of these in SC451 to provide another mechanism to kill these cells if needed.

Anti-CD47 Administration Results in the Rapid Clearance of Hypoimmune NHP iPSCs in Vitro

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Blocking of CD47 in vivo results in killing of hypoimmune iPSCs (as visualized by luminescence of live cells) in NSG mice (n=5) with adoptive transferred human NK cells.

These results have been confirmed in vivo as illustrated above in the allogeneic HIP islet transplantation experiment conducted in a diabetic NHP.

CD47 Overexpression is Differentiated in Inhibiting “Missing Self” Response Relative to Other Approaches

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Our ex vivo Cell Engineering Pipeline

Allogeneic T Cell Programs (SC291, SC262, SC255)

Our allogeneic T cell programs utilize T cells from healthy donors to generate CAR T therapies for various targets, including CD19, a protein expressed on the cell surface of B-cell malignancies, for the potential treatment of patients with relapsed and/or refractory B-cell- malignancies and autoimmune diseases.

We believe that applying our hypoimmune technology to allogeneic T cells will enable us to create differentiated allogeneic CAR T therapies.

We believe our allogeneic T cell programs are potentially disruptive programs that could address the limitations of adoptive T cell therapy for cancer.

Specifically, as part of our allogeneic T cell programs, we have the opportunity to perform multiple gene edits in a T cell, which may allow us to make intentional modifications to control T cell function or deliver more complex chimeric receptors and signal integration machinery to enable the T cell to distinguish tumor cells based on surface antigen combinations and improve the specificity of targeting.

These approaches may prove especially valuable in targeting solid tumors, which have remained largely refractory to CAR T approaches to date.

We also have developed a scaled manufacturing process that we believe we can rapidly leverage to manufacture allogeneic CAR T cells across multiple targets.

Our most advanced product candidate is SC291, a CD19-directed allogeneic CAR T program.

We are currently enrolling and dosing patients in the ARDENT trial evaluating SC291 in patients with NHL and CLL.

In addition, in November 2023, we received IND clearance for the clinical study of SC291 in B-cell-mediated autoimmune diseases, including LN, ERL and ANCA-associated vasculitis, which we refer to as the GLEAM trial.

The clinical trial startup activities for the GLEAM trial are currently underway, and we expect to share clinical data in 2024.

In January 2024, we received IND clearance to evaluate SC262, a CD22-directed allogeneic CAR T, for the treatment of patients with relapsed and/or refractory B-cell malignancies who have received prior CD19-directed CAR T therapy, which we refer to as the VIVID trial.

Clinical trial startup activities for the VIVID trial are also currently ongoing.

We expect to share data from the VIVID trial in 2024.

SC255, is our B-cell maturation antigen (BCMA)-directed allogeneic CAR T, for the treatment for multiple myeloma (MM).

The SC255 program has completed a battery of pre-clinical tests and is currently gated based on resource availability.

Background on B-Cell Malignancies

B-cell malignancies represent a spectrum of cancers including NHL, CLL, ALL, and MM and result in over 100,000 deaths per year in the United States and Europe.

NHL is the most common cancer of the lymphatic system.

NHL is not a single disease, but rather a group of several closely related cancers.

Over 77,000 cases of NHL are diagnosed annually in the United States, and the most common subtype of NHL overall is diffuse large B-cell lymphoma (DLBCL).

DLBCL, if left untreated, may have survival measured in weeks or months.

Other common subtypes of NHL include mantle cell lymphoma (MCL), follicular lymphoma (FL), and marginal zone B-cell lymphoma (MZL).

CLL is the most common type of leukemia and occurs most frequently in older individuals, with diagnoses in people under 30 years of age occurring only rarely.

Each year, approximately 20,000 patients are diagnosed with CLL in the United States.

Approximately 20 to 25% of CLL patients initially present with high-risk disease.

Median progression-free survival in these high-risk individuals is often less than 12 to 18 months after front-line therapy and less than 12 months in relapsed or refractory (R/R) disease.

ALL is a type of leukemia that results from an uncontrolled proliferation of lymphoblasts, which are immature white blood cells.

Lymphoblasts, which are produced in the bone marrow, cause damage and death by inhibiting the production of normal cells.

Approximately 6,000 patients are diagnosed with ALL in the United States each year, and the vast majority of the approximately 1,500 ALL deaths per year occur in adults.

Approximately 80% of cases of ALL in the United States and Europe are B-cell ALL, which almost always involves cancer cells that express the CD19 protein.

The five-year overall survival rate in ALL adults over the age of 60 is approximately 20%, and the median disease-free survival in patients with R/R ALL after two or more lines of therapy is less than six months.

B-cell ALL is the most common cancer in children.

Although children with ALL fare better than adults, children with R/R disease have poor outcomes.

Because of the frequency of this disease, ALL remains a leading cause of death due to cancer in children.

MM is a cancer of the plasma cells, which are B-cells that have matured to specialize in the production of antibodies, and which typically express the BCMA protein.

MM is a condition in which plasma cells become malignant and grow at an uncontrolled pace.

These cells secrete large quantities of the same antibody, resulting in patient symptoms that result from the myeloma cells crowding out other plasma and bone marrow cells, including increased risk of infection, risk of bone destruction, and kidney disease.

MM is the second most common hematologic malignancy, comprising approximately 2% of all cancers and accounting for over 34,000 new cases per year, with 12,600 deaths estimated to have occurred in 2022 in the United States.

High Mortality in Lymphoma, Leukemia and Multiple Myeloma in United States and EU5

Hematologic malignancies result in a large number of annual death across the United States and Europe.

Only a small fraction of patients have durable remissions following CAR T therapy.

Pancreatic Islet Cell Program

SC451 is our hypoimmune PSC-derived pancreatic islet cell product candidate that aims to restore glucose control in patients with T1D patients by transplantation into these patients without the need for immunosuppression.

T1D is a disease of missing pancreatic beta cells, and we believe that transplanting pancreatic islets, which are composed of pancreatic alpha, beta, and delta cells, offers the chance for patients to have normal blood glucose control without insulin, meaningfully improving outcomes for patients with T1D.

Over 20 years of global clinical experience transplanting allogeneic primary pancreatic islets from cadavers support this belief.

After transplant with significant immunosuppression, T1D patients can remain off insulin with well controlled blood glucose for well over a decade.

More recently, several groups have shown that transplant of PSC-derived pancreatic islets along with meaningful immunosuppression can lead to normalization of blood glucose with no need for exogenous insulin.

Because there are relatively few patients for whom long-term immunosuppression is better than insulin, we believe that creating a hypoimmune product, removing the need for immunosuppression, is the key next step in creating a curative and broadly available therapy for patients with T1D.

In December 2024, the first-in-human transplantation of UP421, our HIP-modified allogeneic primary islet cell product, occurred at Uppsala University Hospital in a Phase 1 investigator-sponsored trial (IST).

The IST is designed to evaluate safety, immune evasion, and function of UP421 transplanted intramuscularly without any immunosuppression in a patient with T1D.

Four week and preliminary twelve-week clinical data demonstrate that all primary and secondary endpoints were met.

The study showed no drug product-related adverse events.

Additionally, there was evidence of graft survival by MRI as well as graft survival and function with detectable C-peptide production.

Immunological analysis revealed comprehensive immune evasion of HIP-modified pancreatic islet cells.

The four-week results and preliminary 12-week results are described in greater detail below.

Background on Type 1 Diabetes Mellitus

T1D is an autoimmune disease in which the patient’s immune system destroys its own pancreatic islet cells.

The destruction of these cells leads to complete loss of insulin production and a metabolic disease wherein patients are unable to control their blood glucose levels.

Often called “juvenile diabetes,” T1D disease onset commonly occurs in adolescence.

Beta cells reside in specialized hormone-producing clusters within the pancreas called the islets of Langerhans.

In T1D, activated T lymphocytes infiltrate the islets and selectively kill the beta cells, progressively reducing the body’s capacity to produce insulin.

Once the reserve capacity of beta cells is exhausted, blood glucose rises, and the patient will have a lifelong battle to control blood glucose levels.

Without insulin therapy, T1D is rapidly fatal.

T1D currently affects approximately nine million patients worldwide.

These patients represent a small fraction of the overall global diabetes population, which is estimated to be approximately 540 million.

Current Treatment Landscape and Unmet Need

First-line therapy for NHL typically consists of multi-agent cytotoxic drugs in combination with the monoclonal antibody rituximab.

In younger patients with NHL who have good organ function, high dose chemotherapy followed by stem cell transplantation is often used.

Patients often relapse, however, and since 2017, several therapeutics have been approved in the United States for the treatment of patients with R/R NHL who have received prior therapies.

These approved therapies include CD19 CAR T therapies tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel, CD19 antibody drug conjugate therapy polatuzumab vedotin, and CD19 antibody tafasitamab.

Recently, two autologous CD19 CAR T products have been approved in second-line patients with R/R NHL after proving to be superior to standard of care in pivotal trials, raising the possibility that CD19 CAR T cell therapies may have the potential to have a broader impact for patients with NHL.

Newly diagnosed CLL patients are often treated with targeted therapies such as BTK inhibitors, PIK3 inhibitors, BCL-2 inhibitors, or monoclonal antibodies targeting CD20 or CD52 in combination with chemotherapy.

However, most patients treated with these regimens become refractory.

Numerous drug candidates, including next-generation kinase inhibitors, are in clinical development for refractory patients.

Autologous CD19 CAR T cell therapies are also beginning to progress through clinical trials, with a recent Phase 1/2 study in R/R CLL reporting that it had met its primary endpoint of complete response.

Cure rates for ALL patients have continued to increase over the last four decades, with pediatric ALL cure rates reaching greater than 80% in developed countries.

This progress has been enabled by advances in combination chemotherapy, monitoring of minimal residual disease, expanded use of kinase inhibitors for Philadelphia chromosome-positive ALL, and the recent approval of Kymriah ® for R/R pediatric ALL.

Adult patients fare much worse, however, with 5-year overall survival rates of approximately 20%, and there are still significant challenges managing R/R disease across all age groups.

Multiple therapeutic candidates are in development for R/R patients, including proteasome inhibitors, antimetabolites, JAK inhibitors, and monoclonal antibodies, as well as autologous and allogeneic CAR T candidates.

There are no curative treatment options for MM patients.

First-line therapy for MM consists of induction therapy and high-dose chemotherapy followed by a potential stem cell transplant, and the standard of care for R/R MM includes immunomodulatory agents, proteasome inhibitors, monoclonal antibodies, cytotoxic agents, and hematopoietic stem cell transplant.

Despite the recent advancement in available therapies for MM disease management, the five-year overall survival rate remains at approximately 50%.

Given this significant unmet need, several groups are investigating autologous and allogeneic CAR T cell therapies for R/R MM.

BCMA is among the most promising antigens used to target MM, with two BCMA CAR T therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) having received marketing approval in late-line R/R MM.

Recently, both drugs have been used to dose patients in pivotal clinical studies for patients with R/R MM in earlier lines of therapy, where they outperformed standard of care.

Novel treatments with other mechanisms of action are also undergoing development, including bispecific T cell engagers, next-generation antibodies, and antibody drug conjugates.

As highlighted above, recent therapeutic advances across R/R B-cell malignancies have led to a variety of treatment options and better patient outcomes.

In particular, autologous surface protein-directed CAR T therapies have been highly effective in certain subsets of patients with R/R disease.

However, not all patients have access to these novel therapies, and even if they able to obtain such access, many patients ultimately relapse following treatment and succumb to their cancer, resulting in 100,000 deaths per year in the United States and Europe across these indications.

There are two primary outstanding challenges that have limited utilization of these CAR T therapies and their impact on broader groups of patients:

relapse and manufacturing challenges.

Lack of Response / Relapse .

Only about 50% of patients treated with an approved CD19-directed CAR T therapy will have a complete response and approximately one-third of patients with a complete response will relapse relatively quickly.

The emerging post-approval data from approved CAR T therapies tisagenlecleucel, axicabtagene ciloleucel and lisocabtagene maraleucel indicate that relapse can result from one of two primary factors.

1) The first involves loss of CD19 expression on malignant cells, resulting in tumor escape.

This finding was initially established for ALL and is the cause of relapse after CAR T treatment for roughly half of treated patients.

More recent data indicate that low CD19 expression contributes to the lack of response in a meaningful number of patients with NHL.

CD19 CAR T treatments have recently been tested in pivotal trials in earlier lines of therapy for NHL, which raises the possibility that more patients will be treated with CD19 CAR T therapy and subsequently relapse due to CD19 loss.

Patients with CD19 therapy failure have an extremely poor prognosis, with overall survival measurable in months and virtually no treatment options.

Therefore, the development of CAR T therapies targeting an alternate antigen other than CD19 may provide an opportunity to address this growing unmet need.

Data from several studies have shown that CD22 CAR T treatment has led to complete responses in NHL and ALL patients that failed to reach a complete response or relapsed after CD19 CAR T treatment.

2) The second pattern of relapse relates to suboptimal CAR T cell functionality, such as poor expansion, poor persistence, or T cell exhaustion, resulting in relapse and continued growth of cancer cells that retain the targeted antigen.

Re-infusion with the same CAR T therapy has had limited benefit in these patients, although treatment with a different CAR T therapy has demonstrated some promise in ongoing clinical trials.

Manufacturing .

Because autologous CAR T therapies are patient-specific products, their manufacturing process is complex and requires a significant amount of resources, including time and labor.

Given this, infrastructure and cost considerations and limitations have resulted in limited patient access to these therapies.

Even for patients who are fortunate enough to have access to approved CAR T therapies, delays, commonly of at least one month, resulting from scheduling difficulties and issues that arise during manufacturing may prevent use of and the utility of these therapies in patients with rapidly progressing malignancies.

Certain groups are seeking to overcome access limitations by using healthy donor-derived, or allogeneic, CAR T cells instead of patient T cells to yield “off-the-shelf” therapeutics that can be manufactured consistently.

However, efficacy and durability concerns remain, largely due to the inability to effectively control the HvGR response and the risk of eventual immune rejection of these products by the recipient.

We are developing our ex vivo allogeneic T cell programs to address this HvGR and prevent immune rejection.

Insulin injection is the main treatment option for T1D.

Despite significant advances in types of insulins, glucose monitoring, and insulin pumps, life expectancy for T1D is still approximately 15 years shorter than for people without diabetes.

Patients are at risk of acute complications of hyperglycemia, including diabetic ketoacidosis, coma, and death, as well as hypoglycemic episodes, particularly at night, which can lead to the “dead in bed” syndrome, thought to result from cardiac arrhythmias induced by low glucose.

Long term elevations in blood glucose levels can have particularly devastating effects on arteries and capillaries, resulting in premature myocardial infarction, stroke, limb ischemia, gangrene, kidney failure, and blindness due to diabetic retinopathy.

“Insulin pumps,” which feature a computerized system for sensing blood glucose and delivering appropriate doses of insulin, have improved glycemic control, though data from the FDA indicate that issues with insulin pumps are among the most frequently reported problems in their database.

All current therapies require patients to carefully monitor their dietary intake, which, although inconvenient in adults, is a frequent point of failure in adolescents.

Pancreas transplantation for uncontrollable diabetes was first performed in the 1960s and established the principle that replacing the beta cells (here, in the context of the entire pancreas) could restore physiological glucose control.

Pancreas transplants are complicated surgical interventions, require lifelong immunosuppression, and are limited due to organ availability.

Nevertheless, some 30,000 pancreas transplants have been performed worldwide to date.

Because of these challenges, the biomedical community began exploring pancreatic islet transplantation in the 1970s.

This process requires enzymatic digestion of a donor pancreas and isolation of the islets of Langerhans, followed by delivery of these cells to an appropriate site in the body where the islets can engraft and become well-vascularized.

The major lessons from islet transplantation have been that glucose homeostasis can be restored, insulin independence can be achieved, levels of hemoglobin A1C (a marker of long-term glucose levels) can be normalized, severe episodes of hypoglycemia can be reduced, and the pathology associated with long-term hyperglycemia can halt or even reverse.

As with an organ transplant, patients must undergo chronic immune suppression to prevent immune rejection of the transplanted cells.

Most patients lose glucose control over a period of months to years and eventually become insulin-dependent again, primarily due to immune rejection of the allogeneic islets resulting from an inability to tolerate the significant immune suppression necessary to protect the cell transplant.

Our Pancreatic Islet Cell Program Approach

The goal of our SC451 program is to restore glucose control in T1D patients by transplanting hypoimmune PSC-derived islet cells, including beta cells, without the need for immunosuppression, giving patients physiologically appropriate glucose sensing and insulin secretion.

We believe this therapy could reduce, or even eliminate, hypoglycemia and hyperglycemia in T1D patients, potentially enabling less onerous and costly treatment, fewer complications, a meaningfully improved quality of life, and longer life expectancy.

We focus our efforts around three goals:

(i) deriving highly functional islet cells from PSCs, (ii) using our hypoimmune technology to genetically modify these cells to evade allogeneic immune responses, and (iii) using our hypoimmune technology to genetically modify these cells to evade autoimmune destruction of islet cells.

This strategy requires building on lessons from pancreatic islet transplantation, recent advances in understanding pancreatic islet developmental biology, and our hypoimmune technology.

Deriving islet cells from PSCs has the potential to solve limitations associated with use of a donor pancreas and improve the overall product quality and product consistency.

PSCs have the potential to create a virtually limitless supply of these cells.

Our program uses proprietary differentiation protocols to generate mature islet cells with glucose control comparable to primary human islets, as evidenced by our animal studies.

Finally, we are applying our hypoimmune technology to modify the genomes of the PSCs.

If successful, we believe the hypoimmune genome modifications will protect these PSC-derived islet cells from both autoimmune and allogeneic rejection by the patient’s immune system and potentially remove the need for toxic immunosuppression in transplant recipients.

Hypoimmunity also eliminates the need for physical separation of the islet cells from the rest of the body by a device or encapsulation technology, which may allow for tighter glucose control by eliminating the lag time between glucose sensing and insulin secretion as well as avoiding the fibrotic reaction inherent in encapsulation technologies to date.

Preclinical Data

We are developing a proprietary protocol to differentiate hypoimmune PSCs into mature, glucose-sensitive, insulin-secreting islet cells.

We are exploring ways to optimize the differentiation of islet cells at a greater purity and with superior function compared to published stem cell-based protocols.

The principal function of beta islet cells, the insulin-secreting cells within an islet, is to maintain steady levels of glucose in circulation.

The beta islet cells sense when glucose levels rise in the bloodstream and release insulin in response.

We have observed that our PSC-derived islet populations can respond to glucose and secrete insulin in vitro .

These PSC-derived pancreatic islets were tested in a mouse model of T1D induced by the beta cell toxin, STZ.

When transplanted into the kidney of the T1D mice, these islet cells normalize glucose levels in an equivalent fashion to primary human islets.

The diabetic glucose levels return when the grafts are surgically excised via nephrectomy.

Similar to the human phenotype, T1D mice cannot normalize circulating glucose levels following a glucose injection.

Following transplantation of our islet cells, these mice rapidly normalized blood glucose in an equivalent fashion to both non-T1D mice and T1D mice that received human primary islet transplants.

We have also tested whether hypoimmune modifications to iPSC-derived islet cells can enable evasion of autoimmune rejection.

We approached this question in two ways.

First, we carried out transplantation experiments in the non-obese diabetic (NOD) mouse model, which develops spontaneous T1D due to induction of autoantibodies and autoreactive T cells that kill the islet cells.

We isolated islets from pre-diabetic NOD mice and applied hypoimmune technology to these islets to generate hypoimmune NOD islet cells, which we transplanted into diabetic NOD mice.

When transplanted into NOD mice, unmodified NOD islet cells were rejected within approximately two weeks and had no impact on the diabetes.

By contrast, the hypoimmune NOD islet cells survived and achieved durable glycemic control within two weeks.

In a second set of experiments, we tested whether we would observe similar findings in a human T1D model.

A T1D patient has no functioning islets, so we derived a novel model to test the ability to overcome autoimmune recognition and rejection of these cells.

First, we reprogrammed immune cells from a T1D patient donor into iPSCs.

We then split the iPSCs into two groups – one group to which we applied hypoimmune modifications and one that remained unmodified – before differentiating these iPSCs into islet cells using our differentiation protocol.

This process produced two different cell products for testing:

(i) hypoimmune iPSC-derived islet cells and (ii) unmodified iPSC-derived islet cells.

To simulate the immune environment of a T1D patient, we developed a humanized mouse model (T1D mice) which is populated with immune cells from the same T1D patient donor and in which diabetes is subsequently induced via STZ.

Unmodified iPSC-derived islet cells injected intramuscularly into T1D mice were rejected within nine days without any impact on the mouses ability to control blood glucose.

In contrast, hypoimmune iPSC-derived islet cells survived in T1D mice and resulted in glucose control within two weeks.

To confirm that the immune system was intact and functioning and in these mice, we tested the impact of a subsequent injection of unmodified iPSC-derived islet cells into the mice that had already been injected with hypoimmune iPSC-derived islet cells.

We found that the unmodified iPSC-derived islet cells were rapidly rejected while the hypoimmune iPSC-derived islet cells and the glucose control were preserved.

Together, these data support our belief that our hypoimmune modifications can enable evasion of autoimmune rejection.

Autologous Pancreatic Islet Experiment

Experimental schema for generating a humanized T1D mouse and autologous iPSCs from T1D patient PBMCs.

T1D patient PBMCs were used to generate iPSCs, which were used to generate unmodified and hypoimmune autologous islet cells.

Unmodified iPSC-derived autologous islet cells are cleared by the immune system of the humanized T1D mouse by day 7 and did not restore glycemic control

Hypoimmune iPSC-derived autologous islet cells (injected on left side of mouse) survive for duration of experiment (through day 29) while unmodified iPSC-derived autologous islet cells (injected on right side of mouse at day 15 following injection of hypoimmune iPSC-derived autologous islet cells) are cleared within one week following injection.

Data published in Hu et al., Sci.

15, eadg5794 (2023) 12 April 2023.

HIP-Modified PSC-derived Islet Cells Transplanted into Muscle Persist and Control Blood Glucose in Mice for Greater than 15 Months

Upper left panel:

Single-cell RNA sequencing visualized via a UMAP feature plot showing insulin expression in unedited PSC-derived islet cells.

Analysis reveals high insulin expression across stem cell-derived (sc-) islet cells, with peak expression localized within the sc-beta cell cluster.

Upper right panel:

Glucose-Responsive Human C-Peptide Production by HIP-Modified PSC Islets In Vivo at 51 Weeks Post-Transplant.

HIP-modified PSC islet cells demonstrated sustained functionality through glucose-responsive c-peptide secretion 51 weeks after transplantation (see details of transplantation conditions below).

Mice were fasted for five hours, and plasma was collected via tail-snip before (“pre-glucose,” light gray bar) and 30 minutes after (“post-glucose,” dark gray bar) administration of an intraperitoneal 3 g/kg dextrose bolus.

Human c-peptide levels, measured in picomoles (pM), increased significantly from a baseline of approximately 800 pM to about 1750 pM following glucose stimulation.

Data presented as mean ± S.D.

Long-Term Blood Glucose Control by HIP-Modified PSC Islets.

Graph demonstrates the persistent efficacy of HIP-modified PSC islet cells in controlling blood glucose levels for greater than 64 weeks.

Nonfasted blood glucose levels were measured following transplantation of PSC-derived islet cells (5x10 6 cells/mouse) into the right hindlimb muscle of immunodeficient NSG mice (n=5).

Diabetes was induced by a five-day, low-dose (45 mg/kg) course of STZ beginning two weeks prior to transplantation.

Diabetic (STZ) control mice did not receive PSC-derived islet cells (n=2).

Data is presented as mean ± S.E.M.

We are developing SC451, our HIP-modified PSC-derived islet cell product candidate, to be available as an “off-the-shelf” allogeneic therapy that can be administered intramuscularly without immunosuppression.

Single-cell RNA sequencing analysis of our initial PSC-derived islet cell differentiation process demonstrates consistent production of cell populations comprising approximately 60% beta cells, with the remainder consisting of other islet and neuroendocrine cells.

Single-cell analysis confirms the absence of residual PSCs in the final product.

In vitro studies indicate that HIP modification of PSC-derived islet cells confers immune-evasive properties, which suggests potential utility in the transplantation setting without immunosuppression.

Following intramuscular transplantation into diabetic mice, HIP-modified PSC islet cells have demonstrated survival and function for greater than 64 weeks.

Blood glucose normalization was observed within four weeks post-implantation and maintained throughout the study period.

Analysis shows glucose-responsive human C-peptide production, indicating regulated insulin secretion.

Histological examination at day 458 revealed preserved morphology, C-peptide content, vascularization, and CD47 expression.

No tumor formation or other histologic abnormalities were observed throughout the study duration.