Industry updates from the field of stem cell research and regenerative medicine in December 2023

Business development

Co-development agreement: AbelZeta & AstaZeneca

AbelZeta Pharma (China; https://abelzeta.com), a global clinical-stage biopharmaceutical company focused on the discovery and development of innovative cell therapies for cancer, inflammatory and immunological diseases, has announced an agreement with AstraZeneca (UK; www.astrazeneca.com) to co-develop C-CAR031, an autologous, armored GPC3-targeting chimeric antigen receptor (CAR)-T cell therapy, in hepatocellular carcinoma. C-CAR031 is based on a novel GPC3-targeting CART (AZD5851) designed by AstraZeneca using their TGFβRII dominant negative armoring discovery platform, and is manufactured by AbelZeta in China [1].

Collaboration agreement: elpiscience & astellas

Elpiscience (China; www.elpiscience.com), a privately held, clinical-stage biopharmaceutical company dedicated to developing next-generation immuno-oncology therapies for cancer patients worldwide, and Astellas (Japan; www.astellas.com) has announced a research collaboration and license agreement for novel bi-specific macrophage engagers, ES019, and another programs [2].

Elpiscience's Bispecific Macrophage Engager Platform (BiME^®) is TAA and SIRPα bispecific antibody-based platform to activate tumor-associated macrophage (TAM) phagocytosis killing toward specific TAA expressing tumor cells. BiME shows highly potent phagocytosis due to engagement of the Fc receptor on TAM and the tumor cells via TAA and SIRPα, and blockade of CD47-SIRPα ‘don't eat me’ signaling. This platform is utilized for ES019, an anti-PD-L1/SIRPα bispecific antibody.

TAMs are the most abundant leukocytes within tumor microenvironment of many cancer types and correlate with poor prognosis and immune checkpoint inhibitor resistance. The programs emerging from the BiME platform are expected to offer new options for cancer patients who do not respond to existing cancer immunotherapies, by modulating TAM and reprogramming the tumor microenvironment status.

Elpiscience will receive up to US$37 million, including the upfront payment and license option fees. In addition, Elpiscience will receive research funding from Astellas to advance the programs. After Astellas exercises its option, Elpiscience is eligible to potentially receive more than US$1.7 billion in payments for the achievement of future development, regulatory and commercial milestones. Elpiscience is also eligible to receive single-digit to lower double-digit percent royalty payments on net sales for licensed products per each program.

Collaboration agreement: immunoscape & EDDC

ImmunoScape (Singapore; www.immunoscape.com), a biotechnology company focused on next-generation T-cell receptor (TCR)-based immunotherapies, announced a partnership with the Experimental Drug Development Centre (EDDC; Singapore; www.eddc.sg), a platform for drug discovery and development hosted by the Agency for Science, Technology and Research (A*STAR) [3].

ImmunoScape's core antigen-specific T cell immune profiling technology was developed at A*STAR's Singapore Immunology Network and is exclusively licensed from A*STAR. Since its spinout from A*STAR in 2016, ImmunoScape has developed a cutting-edge, high-throughput, TCR discovery platform that produces a broad and emerging portfolio of novel, safe, and efficacious TCRs against solid tumors.

In this new partnership, ImmunoScape will leverage its catalog of highly potent tumor-specific TCR candidates for the joint development of innovative off-the-shelf TCR-based bispecific molecules with EDDC. These molecules contain two distinct binding sites and are engineered to bind and activate T cells, redirecting them toward tumor sites for interaction with cells expressing the unique tumor-specific antigen through the TCR. This approach enables the patient's own T cell repertoire to selectively eliminate cancer cells. EDDC will apply its expertise in therapeutic protein design and antibody engineering to develop these novel TCR-based bispecific molecules.

Collaboration agreement: immunoscape & MiNK

ImmunoScape (Singapore; www.immunoscape.com), a biotechnology company focused on next-generation TCR-based therapeutics, and MiNK Therapeutics (NY, USA; https://minktherapeutics.com), a clinical stage biopharmaceutical company specializing in the discovery, development and commercialization of allogeneic, off-the-shelf, invariant natural killer T (iNKT) cell targeting therapies, today announced a collaboration agreement to discover and develop next-generation TCR therapies against novel targets in solid tumors [4]. The combined efforts of both companies aim to accelerate the development of TCR-based therapies against novel targets in T cells, iNKT cells, and other modalities, potentially offering new therapeutic approaches for diverse cancer indications.

ImmunoScape's unique Deep Immunomics platform enables high-throughput and sensitive screening of T cells against relevant tumor targets for the rapid discovery of rare, therapeutically-relevant TCRs. MiNK Therapeutics has a proprietary library of phospho-peptide neoantigens derived from a wide range of solid tumors and hematologic malignancies. In this collaborative effort, ImmunoScape will leverage their capabilities in multiplex antigen screening and in-depth T cell profiling to identify relevant TCRs targeting the library of phospho-peptide antigens. MiNK Therapeutics will further characterize these tumor-specific TCRs, leveraging its proprietary capabilities to analyze and select TCR candidates for optimal tumor targeting.

Partnership agreement: atara & pierre fabre

Atara Biotherapeutics (CA, USA; www.atarabio.com), a T-cell immunotherapy company, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, has announced the closing of the expanded global partnership with Pierre Fabre Laboratories (France; www.pierre-fabre.com/en) for tabelecleucel (tab-cel^® or EBVALLO™) [5]. Building on the earlier partnership announced in October 2021 to commercialize tab-cel in Europe, this transaction provides Pierre Fabre Laboratories with the development, manufacturing, and commercialization rights for tab-cel in USA and all remaining markets.

With the closing of the transaction, Atara will receive approximately USD 27 million in cash upfront and initial inventory purchase. Under the agreement, Atara has the potential to receive up to a total of USD 640 million and significant double-digit tiered royalties on net sales, including up to USD 100 million in potential regulatory milestones through Biologics License Application (BLA) approval. In addition, Pierre Fabre Laboratories will reimburse Atara for expected tab-cel global development costs through the BLA transfer, and purchase future tab-cel inventory through the manufacturing transfer date.

Substantially all tab-cel manufacturing, clinical, and regulatory activities are planned to transition from Atara to Pierre Fabre Laboratories at the time of BLA transfer.

Service agreement: charles river & CELLphenomics

Charles River Laboratories (MA, USA; www.criver.com) has entered into an agreement with CELLphenomics (Germany; www.cellphenomics.com), a service-based biotechnology company that is using 3D hydrogel technology to advance the understanding of the tumor microenvironment and predict therapeutic efficacy [6]. This enhanced offering will provide Charles River clients with access to CELLphenomics' proprietary 3D tumor model platform, PD3D^®, expanding Charles River's 3D in vitro testing services to further optimize oncological approaches for its clients.

CELLphenomics' core competency is the establishment and cultivation of complex patient-derived 3D cell culture models (PD3D) from various solid tumor tissues. These highly reliable, well-annotated and predictive preclinical PD3D models robustly recapitulate the biological properties of the donor tissue, including key histopathological features and genomic makeup. They are a powerful tool for disease modeling, biomarker and drug discovery. CELLphenomics' continuously growing biobank comprises more than 500 complex in vitro models from more than 20 tumor entities, and offers the world's largest collection of complex in vitro models of rare and ultra-rare tumors like sarcomas or thymomas.

CELLphenomics has developed a custom mid-throughput screening platform that blends complex cell culture models with advanced automation and a streamlined analysis pipeline. The proprietary, precision medicine PD3D platform offers mid-throughput efficacy testing, drug combination screening, toxicity profiling, target validation, drug sensitivity correlation with clinical response, and biomarker identification.

Strategic partnership: Taiwan Bio & TRACT

Taiwan Bio (Taiwan; https://twbio-thera.com/language/en/) and TRACT Therapeutics (IL, USA; www.tracttherapeutics.com) have announced a new strategic partnership to advance a cellular therapy to revolutionize the prevention of allograft rejection in solid organ transplant [7]. The partners will launch a multicenter phase II clinical trial investigating the reduction of immunosuppressant drugs in living donor kidney transplant recipients in both USA and Taiwan.

This partnership leverages Taiwan Bio's world-class expertise in cellular therapy manufacturing and TRACT Therapeutics' innovative immune modulating regulatory T cell therapy platform. By combining their strengths, the companies are set to explore new frontiers in enabling allogeneic tissue transplant with a focus on enhanced patient outcomes and improved quality of life. The upcoming phase II trial builds upon the promising results from a phase 1 study that demonstrated an excellent safety profile and encouraging efficacy signals with TRACT's autologous Treg product, TregCel™.

Achievements, launches…

Carisma & Moderna

Carisma Therapeutics (PA, USA; www.carismatx.com), a clinical-stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, has announced the nomination of its first lead candidate under the collaboration with Moderna (MA, USA; www.modernatx.com) [8]. This first lead candidate will target an antigen present on a solid tumor with significant unmet medical need. This strategic collaboration brings together Carisma's chimeric antigen receptor macrophage (CAR-M) platform with Moderna's messenger RNA (mRNA) and lipid nanoparticle (LNP) technologies to generate and develop in vivo CAR-M therapeutics for oncology.

Charles river

Charles River Laboratories (MA, USA; www.criver.com) has passed back-to-back audits from both the US FDA and the Health Products Regulatory Authority (HPRA), on behalf of the European Medicines Agency (EMA) [9]. The facility was the first North American contract development and manufacturing organization (CDMO) to be approved by the EMA to commercially manufacture an allogeneic cell therapy drug product.

Seattle children's & BrainChild Bio

Seattle Children's (WA, USA; www.seattlechildrens.org) has launched BrainChild Bio (WA, USA; www.brainchildbio.com) to accelerate the advancement of CAR-T cell therapies in central nervous system (CNS) tumors [10]. BrainChild Bio will be granted an exclusive license to novel CAR T-cell technology for CNS tumors developed at Seattle Children's. Seattle Children's has provided the initial equity funding for BrainChild Bio which will operate as an independently managed corporation.

Since 2012, Seattle Children's Therapeutics has designed, manufactured and launched a robust portfolio of immunotherapy clinical trials for leukemia and lymphoma, brain tumors, and solid tumors, enrolling more than 500 patients. The launch of BrainChild Bio is a natural progression of Seattle Children's Therapeutics' goal to expand access to potentially life-changing therapies through collaborations with biotech companies.

BrainChild Bio's initial CAR T-cell therapy program will focus on pediatric brain tumors, prioritizing diffuse intrinsic pontine glioma (DIPG), an incurable type of childhood cancer that forms in the brainstem. The company's clinical programs will be accelerated by the foundational work at Seattle Children's Therapeutics, which consists of four clinical trials designed to validate the safety and confirm early efficacy of several different targets for CAR T-cell therapy in pediatric CNS tumors, with preliminary results planned for presentation at a scientific forum in 2024. The BrainChild-04 clinical study,1 was initiated this year and continues to evaluate four different targets in a single CAR T-cell therapy. Following the achievement of clinical proof-of-concept in DIPG, BrainChild Bio plans to seek pediatric registration for DIPG and then extend the therapeutic application of its novel CAR T-cell therapies to target additional difficult-to-treat pediatric and adult brain tumors, including glioblastoma and brain metastases.

Seattle Hub for synthetic biology

The Allen Institute (WA, USA; https://alleninstitute.org), the CZI (CA, USA; https://chanzuckerberg.com), and the University of Washington (WA, USA; www.washington.edu) have launched the Seattle Hub for Synthetic Biology: a landmark collaboration that will build new technologies to record the history of cells over time [11]. These technologies will help researchers crack the code and understand not just end point measurements of cells and genes in health and disease but the dynamics of their trajectories over time. The Seattle Hub for Synthetic Biology brings together the best of large-scale science and philanthropy with proven academic power to develop, refine and share this paradigm-shifting single-cell technology.

Clinical trials

Immune cells

Obsidian

Obsidian Therapeutics (MA, USA; https://obsidiantx.com), a clinical-stage biotechnology company pioneering engineered cell and gene therapies, has announced positive top-line results from the ongoing first-in-human, phase 1 clinical trial evaluating the safety and efficacy of OBX-115, Obsidian's lead engineered tumor-infiltrating lymphocyte (TIL) cell therapy candidate, in patients with metastatic melanoma that has relapsed and/or is refractory to prior immune checkpoint inhibitor (ICI) therapy [12,13].

OBX-115 is an investigational novel IL2-sparing engineered TIL cell therapy armed with pharmacologically regulatable membrane-bound IL15 designed to enhance persistence, anti-tumor activity, and clinical safety of TIL cell therapy relative to unengineered TIL therapy plus high-dose IL2.

The first six patients treated with OBX-115 were heavily pre-treated, and all had progressed on anti-PD-1 and anti-CTLA-4 therapy with disease that was primary-resistant to ICI therapy. At a median follow-up of 18 weeks (1 December 2023, data cut-off), a 50% investigator-assessed objective response rate (ORR) using RECIST 1.1 criteria was observed. Two complete responses and one partial response were achieved, with a disease control rate (DCR) of 100%.

In addition, Obsidian announced that it has enrolled the first patient in its multicenter phase 1/2 study of advanced or metastatic melanoma resistant to ICI therapy [14]. This study allows multiple centers to have access to OBX-115 and is currently enrolling patients.

Regulations, approvals, acquisitions…

Green light

CARsgen

CARsgen Therapeutics Holdings Limited (China; www.carsgen.com), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, has announced that the US FDA has granted Investigational New Drug (IND) clearance for CT071, an autologous CAR T-cell therapy candidate targeting GPRC5D, for the treatment of patients with relapsed/refractory multiple myeloma (r/r MM) or relapsed/refractory primary plasma cell leukemia (r/r PCL) [15,16].

GPRC5D is emerging as an important target in the landscape of MM, a common but incurable hematologic malignancy characterized by the uncontrolled proliferation of plasma cells. The notable overexpression of GPRC5D on the surface of malignant plasma cells, coupled with its limited presence on normal tissues, makes GPRC5D an ideal candidate for the treatment of MM and PCL. CT071 incorporates a fully human single-chain variable fragment (scFV) developed by CARsgen, specifically designed to target GPRC5D.

CT071 is manufactured with CARsgen's proprietary CARcelerate™ platform, which shortens the manufacturing time to less than 2 days and therefore yields younger, healthier, and possibly more potent CAR T cells compared with conventional manufacturing. The improved manufacturing efficiency also enhances the supply capacity, reduces the manufacturing costs, and expedites the availability of the product to the patients.

An investigator-initiated trial (IIT) is already under way in China to assess the safety and efficacy of CT071 in treating relapsed/refractory MM or PCL. Preliminary clinical data from the IIT shows an acceptable safety profile with preliminary efficacy.

In a separate press release, CARsgen has announced that CT011, an autologous CAR T-cell product candidate against GPC3, has achieved IND clearance from the National Medical Products Administration (China; NMPA; http://english.nmpa.gov.cn/) for patients with GPC3-positive stage IIIa hepatocellular carcinoma who are at high risk of recurrence after surgical resection [17].

Chiesi

Chiesi Global Rare Diseases, a business unit of the Chiesi Group (MA, USA; www.chiesi.com) established to deliver innovative therapies and solutions for people affected by rare diseases, has announced that the US FDA approved FILSUVEZ^® (birch triterpenes) topical gel for the treatment of partial thickness wounds in patients 6 months and older with Junctional Epidermolysis Bullosa (JEB) and Dystrophic Epidermolysis Bullosa (DEB) [18]. FILSUVEZ is the first approved treatment for wounds associated with JEB, a rare, moderate-to-severe form of EB with blisters beginning in infancy. FILSUVEZ joined the Chiesi portfolio as part of the agreement reached during the acquisition of Amryt Pharma in January 2023.

EB is a debilitating inherited skin disease that causes a person's skin to be so fragile it can be injured just from touch. This rare, chronic, and distressing disorder affects infants, children and adults and is intensely painful; recurrent blistering and chronic wounds can result in intolerable pain with limited mobility. Living with EB entails daily challenges to navigate, including slow-healing wounds at risk of infection and painful dressing changes.

FILSUVEZ contains a dry extract from two species of birch bark consisting of naturally occurring substances known as triterpenes, including betulin, betulinic acid, erythrodiol, lupeol and oleanolic acid. FILSUVEZ is administered at home, allowing for integration into existing treatment routines. It is applied topically to the wound at each dressing change.

bluebird bio

bluebird bio (MA, USA; www.bluebirdbio.com) has announced that the US FDA has approved LYFGENIA (lovotibeglogene autotemcel), also known as lovo-cel, for the treatment of sickle cell disease in patients ages 12 and older who have a history of vaso-occlusive events [19,20]. LYFGENIA is a one-time gene therapy that has the potential to resolve vaso-occlusive events and is custom-designed to treat the underlying cause of sickle cell disease.

Lyfgenia uses a lentiviral vector (gene delivery vehicle) for genetic modification and is approved for the treatment of patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events. With Lyfgenia, the patient's blood stem cells are genetically modified to produce HbA, a gene-therapy derived hemoglobin that functions similarly to hemoglobin A, which is the normal adult hemoglobin produced in persons not affected by sickle cell disease. Red blood cells containing HbA have a lower risk of sickling and occluding blood flow. These modified stem cells are then delivered to the patient.

LYFGENIA will be available through bluebird's established national network of Qualified Treatment Centers beginning in Q1 2024 ‘my bluebird support’ (www.mybluebirdsupport.com) [21]. Patient services program will provide personalized support for patients and their families throughout their treatment journey. Price of LYFGENIA reflects its value as a potentially curative gene therapy for sickle cell disease through durable production of anti-sickling adult hemoglobin (HbAT87Q) and resolution of vaso-occlusive events.

Vertex & CRISPR Therapeutics

Vertex Pharmaceuticals (MA, USA; www.vrtx.com) and CRISPR Therapeutics (Switzerland; https://crisprtx.com) have announced that the US FDA has approved CASGEVY™ (exagamglogene autotemcel [exa-cel]), a CRISPR/Cas9 genome-edited cell therapy, for the treatment of sickle cell disease in patients 12 years and older with recurrent vaso-occlusive crises [20,22].

Casgevy is the first FDA-approved therapy utilizing CRISPR/Cas9, a type of genome editing technology. Patients' hematopoietic stem cells are modified by genome editing using CRISPR/Cas9 technology and the modified cells are transplanted back into the patient where they engraft within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. In patients with sickle cell disease, increased levels of HbF prevent the sickling of red blood cells.

Acquisitions

AstraZeneca & Gracell

AstraZeneca (UK; www.astrazeneca.com) has entered into a definitive agreement to acquire Gracell Biotechnologies (China; www.gracellbio.com), a global clinical-stage biopharmaceutical company developing innovative cell therapies for the treatment of cancer and autoimmune diseases, furthering the AstraZeneca cell therapy ambition [23].

The proposed acquisition will enrich AstraZeneca's growing pipeline of cell therapies with GC012F, a novel, clinical-stage FasTCAR-enabled BCMA and CD19 dual-targeting autologous chimeric antigen receptor T-cell (CAR-T) therapy, a potential new treatment for multiple myeloma, as well as other haematologic malignancies and autoimmune diseases including systemic lupus erythematosus (SLE).

Gracell will operate as a wholly owned subsidiary of AstraZeneca, with operations in China and the USA. Combined, the upfront and potential contingent value payments represent, if achieved, a transaction value of approximately US$1.2bn.

Capital Market & Finances

bluebird bio

bluebird bio (MA, USA; www.bluebirdbio.com) announced the pricing of its underwritten public offering of 83,333,333 shares of its common stock at a public offering price of US$1.50 per share, before deducting underwriting discounts and commissions. bluebird also granted the underwriters a 30-day option to purchase up to an additional 12,499,999 shares of its common stock at the public offering price per share, less underwriting discounts and commissions [24]. The gross proceeds from the public offering are expected be US$125 million, before deducting underwriting discounts and commissions and offering expenses payable by bluebird and assuming no exercise of the underwriters' option to purchase additional shares of common stock. All shares in the offering are to be sold by bluebird.

bluebird intends to use the net proceeds of the offering to support commercialization and manufacturing for its three approved gene therapies, ZYNTEGLO, SKYSONA and LYFGENIA; and to fund working capital and other general corporate purposes.

FujiFilm

FUJIFILM Corporation (Japan; www.fujifilm.com) has announced the investment of US$200 million in two subsidiaries to significantly expand global cell therapy contract development and manufacturing (CDMO) capabilities [25]. The investment will enable Fujifilm to support the expanding cell therapy market which is anticipated to grow by more than 30% per year up from US$3.3 billion in FY2022.

The US$200 million investment in cell therapy manufacturing capabilities will strengthen Fujifilm's manufacturing capacity to support iPSC-derived cell therapies, as well as cytotoxic T lymphocyte (CTL), chimeric antigen receptor (CAR), T-cell receptor (TCR), natural killer (NK) and tissue-derived therapies. The full site will be operational in spring 2026.

Shinobi

Shinobi Therapeutics (Japan; www.shinobitx.com), the biotechnology company developing a new class of immune evasive iPS-T cell therapies, has announced that it has closed a US$51 million Series A financing [26]. Shinobi will use the funds to advance its ‘Katana’ iPS-T cell therapy platform and progress its first program to treat GPC3+ solid tumor cancers toward the clinic. Shinobi's unique approach is to first edit iPSCs to become highly immune evasive before they are differentiated with the company's proprietary Katana technology to create CD8αβ iPS-T cells.