Industry updates from the field of stem cell research and regenerative medicine in January 2024

Business development

Co-development agreement: IASO Bio & Umoja

IASO Biotherapeutics (China; www.iasobio.com), a biopharmaceutical company engaged in discovering, developing, manufacturing and marketing innovative cell therapies and antibody products, has announced a new set of collaborations with Umoja Biopharma (WA, USA; http://umoja-biopharma.com), an immunotherapy company creating off-the-shelf treatments that aim to extend the reach and effectiveness of chimeric antigen receptor (CAR) T-cell therapies in oncology and autoimmunity, for the development and commercialization of novel ex vivo and in vivo cell and gene therapies [1].

Under the terms of the collaborations, IASO Bio will receive exclusive access to the rapamycin-activated cytokine receptor (RACR™) platform, Umoja's synthetic cytokine receptor technology, for the development of two ex vivo induced pluripotent stem cells (iPSCs)-derived CAR-bearing cell therapies. IASO will be responsible for worldwide product development, manufacturing, regulatory and commercialization of both ex vivo products. In exchange, Umoja will receive exclusive rights to CAR cassettes for two targets for the advancement of two in vivo product candidates incorporating VivoVec™, Umoja's proprietary lentiviral in vivo gene delivery technology.

Licensing agreement: BlueRock & FUJIFILM

BlueRock Therapeutics (MA, USA; www.bluerocktx.com), a clinical stage cell therapy company and wholly owned, independently operated subsidiary of Bayer (Germany; www.bayer.com), has exercised its option to exclusively license OpCT-001, an iPSC-derived cell therapy candidate for the treatment of primary photoreceptor diseases, from FUJIFILM Cellular Dynamics (WI, USA; www.fujifilmcdi.com) and Opsis Therapeutics (WI, USA; https://opsistx.com) [2]. OpCT-001 is the lead cell therapy candidate being developed under the strategic R&D collaboration between BlueRock, FUJIFILM Cellular Dynamics and Opsis Therapeutics that was forged in 2021. Under the terms of the agreement, FUJIFILM Cellular Dynamics and Opsis Therapeutics receive an undisclosed license fee and are eligible to receive payments upon achievement of certain development and commercial milestones.

Partnership agreement: CN Bio & Altis

CN Bio (UK; https://cn-bio.com) and Altis Biosystems (NC, USA; www.altisbiosystems.com), companies focused on in vitro human organ models that optimize the accuracy and efficiency of drug development, have announced a strategic partnership [3]. Through this partnership, Altis' human RepliGut Planar-Jejunum model will be integrated with CN Bio's PhysioMimix Liver-on-a-Chip to create a primary human microphysiological system (MPS), with interorgan communication to mimic the oral drug administration route. Harnessing both companies' organ-specific expertise, the MPS provides preclinical researchers with a robust and reliable gut/liver model for enhancing the in vitro to in vivo translatability of oral bioavailability.

Strategic collaboration: AbbVie & Umoja

AbbVie (IL, USA; www.abbvie.com), and Umoja Biopharma (WA, USA; http://umoja-biopharma.com), an early clinical stage biotechnology company, have announced two exclusive option and license agreements to develop multiple in situ generated CAR-T-cell therapy candidates in oncology using Umoja's proprietary VivoVec™ platform [4]. The first agreement provides AbbVie an exclusive option to license Umoja's CD19 directed in situ generated CAR-T-cell therapy candidates. This includes UB-VV111, Umoja's lead clinical program for hematologic malignancies currently at the IND-enabling phase. Under the terms of the second agreement, AbbVie and Umoja will develop up to four additional in situ generated CAR-T-cell therapy candidates for discovery targets selected by AbbVie.

Under the terms of the two agreements, Umoja received upfront payments and an equity investment from AbbVie.

Achievements, launches…

Atara & Pierre Fabre

Atara Biotherapeutics (CA, USA; www.atarabio.com), a T-cell immunotherapy company, leveraging its allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, and Pierre Fabre Laboratories (France; www.pierre-fabre.com/en-us), responsible for worldwide commercialization of tabelecleucel (tab-cel^® or EBVALLO™), have published the data from the pivotal Phase III ALLELE study of tab-cel, approved in the EU and the UK in adults and children 2 years of age and older with relapsed or refractory (r/r) EBV positive post-transplant lymphoproliferative disease following solid organ or hematopoietic cell transplant [5–7].

Danaher: IGI Beacon

Danaher Corporation (D.C., USA; www.danaher.com) and the Innovative Genomics Institute (IGI; CA, USA; https://innovativegenomics.org) have launched a collaborative center to develop gene-editing therapies for rare and other diseases, with a goal of creating a new model for future development of a wide range of genomic medicines [8]. The center, known as the Danaher-IGI Beacon for CRISPR Cures, aims to use CRISPR-based gene editing to permanently address hundreds of diseases with a unified research, development and regulatory approach.

The Innovative Genomics Institute is a joint effort between the Bay Area's leading scientific research institutions, UC Berkeley and UC San Francisco, with affiliates at UC Davis, Lawrence Berkeley National Laboratory, Lawrence Livermore National Laboratory, Gladstone Institutes and other institutions.

eGenesis & PorMedTec

eGenesis, a biotechnology company developing human-compatible organs and cells for the treatment of organ failure (MA, USA; https://egenesisbio.com), and PorMedTec (Japan; https://pormedtec.com/en/), a global leader in porcine embryology, have successfully produced genetically engineered porcine donors in Japan for use in transplantation [9]. As part of a collaboration between the two companies, genetically engineered porcine cells developed by eGenesis were provided to PorMedTec for production using the somatic cell nuclear transfer, or cloning, process. Cells provided by eGenesis carry the same edits used for its lead organ candidate in development in the US. These edits include knock out of three genes involved in the synthesis of glycan antigens implicated in hyperacute rejection, insertion of seven human transgenes involved in the regulation of several pathways that modulate rejection: inflammation, innate immunity, coagulation and complement and inactivation of the endogenous retroviruses in the porcine genome. The company's landmark preclinical study using kidneys with these genetics was recently published [10].

FUJIFILM

FUJIFILM Wako Pure Chemical Corporation (Japan; www.fujifilm.com) has launched the MassivEV™ EV Purification Column PS and MassivEV™ Purification Buffer Set, products designed for high-purity and high-efficiency mass purification of extracellular vesicles (EVs) to support exosome research [11].

EVs are lipid bilayer-delimited vesicles released by cells containing a variety of physiological active substances including lipids, nucleic acids and proteins involved in intercellular communication that play a role in disease and health. EVs secreted by mesenchymal stem cells are reported to have a therapeutic effect on various diseases and skin conditions, prompting active R&D in the areas of healthcare, cosmetics and food. In the medical field, there is a growing need for mass purification of high-quality EVs for application in diagnostic and drug-delivery pharmaceutical manufacturing processes.

The MassivEV EV Purification Column PS and the MassivEV Purification Buffer Set are capable of EV purification from liter-scale cell culture supernatants compatible with safety and pharmacological testing. The products are based on the PS Affinity method, FUJIFILM Wako Pure Chemical's proprietary EV isolation technique. The MassivEV products can achieve efficient single-step purification of EVs in higher purity than those obtained with the conventional mass EV purification method, which requires multiple purification steps.

FUJIFILM Wako Pure Chemical is working to achieve compliance with the Standards for Biological Ingredients6 and ISO203997 and promoting further process development for future applications in commercial-scale manufacturing.

Kyverna

Kyverna Therapeutics (CA, USA; www.kyvernatx.com), a clinical-stage biopharmaceutical company focused on developing cell therapies for patients suffering from autoimmune diseases, has published a paper describing its proprietary manufacturing process that utilizes less than 300 ml of whole blood from a blood draw instead of apheresis for the collection of T cells from patients undergoing CAR T-cell therapy [12,13].

Leukapheresis – a specific type of apheresis – is a conventional starting material for CAR T-cell therapy. The procedure poses challenges due to its length and invasiveness, cost, limited capacity of apheresis beds and resource constraints at the collection center. Currently, apheresis requires patients to be connected to a cell separator to collect the T cells by centrifugation and returns the remaining blood components into the body. The procedure must be performed at specialized centers and can last up to 5 h.

Clinical trials

Immune cells

Indapta

Indapta Therapeutics (TX, USA; https://indapta.com), a privately held biotechnology company developing IDP-023, a natural killer (NK) cell therapy for the treatment of cancer, has initiated treatment of the first patients in its phase I trial in multiple myeloma and non-Hodgkin's lymphoma [14]. Indapta's universal, allogeneic NK cell therapy platform consists of a potent subset of naturally occurring NK cells, known as ‘G minus’ NK cells, or ‘g-NK’ that markedly improve the cancer killing power of monoclonal antibody therapy, without the need for genetically engineering the cells. G-NK cells arise from epigenetic changes resulting from exposure to cytomegalovirus. To generate IDP-023, Indapta preferentially expands g-NK cells from healthy donors with increased numbers of g-NK cells. Indapta's off-the-shelf g-NK cell therapy is further differentiated from other NK cell therapies in that it is a cryopreserved product with low variability. Indapta's g-NK are capable of releasing dramatically more immune activating cytokines and cancer-killing compounds than conventional NK cells.

PeproMene

PeproMene Bio (CA, USA; https://pepromenebio.com), a clinical-stage biotech company developing novel therapies to treat cancers and immune disorders, has announced that the cohort 1 first patient treated in its Phase I relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) clinical trial of PMB-CT01 (BAFFR-CAR T cells) has reached complete remission at 1-month post treatment [15,16].

The patient had a r/r B-ALL after prior treatment with chemotherapy and blinatumomab. His relapsed disease was both CD19- and CD22-negative, implying very limited available therapeutic options for him.

PMB-CT01 is a first-in-class BAFFR-targeted, autologous CAR T-cell therapy. BAFF-R (B-cell activating factor receptor), a TNF receptor superfamily member, is the main receptor for BAFF expressing almost exclusively on B cells. Since BAFF-R signaling promotes normal B-cell proliferation and appears to be required for B-cell survival, it is unlikely tumor cells could escape immune responses via loss of BAFF-R antigen. This unique characteristic makes BAFFR-CAR T therapy a great potential treatment of B-cell malignancies. BAFFR-CAR T was constructed using the anti-BAFF-R scFv (single-chain fragment variable) antibodies with the second generation signaling domains containing CD3ζ and 4-1BB.

Other

Aegle

Aegle Therapeutics (MA, USA; www.aegletherapeutics.com), a company developing EV-based therapies to treat dermatological conditions, has announced positive 12-week data for the first patient enrolled in a phase I/IIa clinical trial of AGLE-102™ for the treatment of severe second-degree burns [17,18].

The first patient was treated with a single topical dose of AGLE-102 within 48 h of burn injury. The patient achieved 99% epithelialization of the burn wound and had a significant reduction in edema within seven days of treatment. Subsequent doses of AGLE-102 were not required.

AGLE-102 is an investigational product comprised of extracellular vesicles isolated from allogeneic stem cells using Aegle's proprietary and patented methods. The product is a composite of native EVs and their associated complex assemblies of biologic molecules such as proteins, peptides, ligands and nucleic acids that have the potential to induce a wide variety of effects in recipient cells, including reducing inflammation, modulating the immune system and promoting regenerative healing.

CorrectSequence

CorrectSequence Therapeutics (China; www.correctsequence.com/?lang=en), a company using innovative transformer Base Editing (tBE) technology to help people with severe diseases, has announced positive results of its base editing therapy for transfusion-dependent β-thalassemia, CS-101 [19]. The Investigator-Initiated Trial of CS-101 has successfully cured the first treated patient with transfusion-dependent β-thalassemia, resulting in sustained transfusion-free for more than 2 months. Eight weeks after CS-101 treatment, the patient's fetal hemoglobin level has increased to ∼95 g/l, accounting for ∼81% of total hemoglobin.

eGenesis & OrganOx

eGenesis, a biotechnology company developing human-compatible organs and cells for the treatment of organ failure (MA, USA; https://egenesisbio.com), and OrganOx (UK; www.organox.com), a medical device company with a focus on the therapeutic applications of isolated organ perfusion, have announced the successful completion of an extracorporeal perfusion of a brain-dead research donor using a genetically engineered porcine liver [20]. The donor was the first to be enrolled in the ongoing PERFUSE-2 study.

The perfusion was performed using the eGenesis liver, EGEN-5784, connected to the OrganOx extracorporeal liver cross-circulation (ELC) device to enable circulation of the donor's blood through the porcine liver. Stable blood flow, pressure and pH were maintained throughout the procedure, in addition to robust bile production. No evidence of rejection was observed. The perfusion was electively stopped per protocol at 72 h with the liver appearing healthy.

The PERFUSE-2 study is being conducted to evaluate the feasibility of using this liver perfusion system to support patients suffering from liver failure.

RION

RION (MN, USA; www.riontx.com), a clinical-stage exosome therapeutic company, has officially commenced a Phase IIA study aimed at assessing the efficacy and safety of its exclusive exosome regenerative therapeutic, known as Purified Exosome Product™ (PEP™), for the management of Diabetic Foot Ulcers [21]. RION's PEP is a shelf stable product in a lyophilized powder derived from human platelets that contains stabilized platelet-derived exosomes designed to promote cell growth and formation of new blood vessels, while also reducing inflammation and protecting cells.

Regulations, approvals, acquisitions…

Regulations

FDA

Based on cases it had received from clinical trials and post-marketing surveillance, the US FDA (MD, USA; www.fda.gov) is now requiring label updates for all six commercial CAR-T therapies [22–29]. Specifically, the agency wants the companies to include a paragraph in those boxed warnings to say, “T-cell malignancies may occur following treatment with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including,” followed by the product's name. The same language is also required as part of the ‘secondary malignancies’ item in the less prominent ‘Warnings and Precautions' section of a drug's label.

A few days later, the FDA Center for Biologics Evaluation and Research (CBER) Office of Therapeutic Products (OTP) has issued a guidance document entitled “Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products” addressing manufacturing, nonclinical, and clinical considerations specific to CAR T cell products [30].

Green light

CARsgen

CARsgen Therapeutics (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 CT011, an autologous CAR T-cell product candidate against GPC3, has achieved Investigational New Drug (IND) clearance from the National Medical Products Administration (NMPA) for patients with GPC3-positive stage IIIa hepatocellular carcinoma who are at high risk of recurrence after surgical resection [31].

CellVax

CellVax Therapeutics (FL, USA; https://cellvx.com) has received clearance of its IND by the US FDA for their personalized cancer immunotherapy FK-PC101, intended to treat prostate cancer patients who have a high risk of recurrence after prostatectomy [32]. It consists of patient's own tumor cells which are collected during surgery, then modified in the laboratory. The modified cells express MHC Class II on their surface, which are then irradiated to make them replication incompetent and delivered as an individualized immunotherapy.

GC Cell

GC Cell (Korea; https://gccell.com/eng/main), a cell therapy company, has announced the approval from both the Australian Human Research Ethics Committee (HREC) and the Korean Ministry of Food and Drug Safety (MFDS) for a phase I IND trial for its AB-201 cancer treatment, a HER2 targeted CAR NK cell therapy [33].

AB-201, a novel CAR NK cell therapy targeting solid tumors, represents a breakthrough in cancer immunotherapy, capable of killing malignant cells. While existing NK cell treatments typically dissipate within a few weeks, AB-201 has demonstrated persistence for over 2 months in preclinical studies, highlighting its potential in managing long-term, advanced cancers. A multi-country study, the phase I trial will evaluate safety and efficacy in 48 patients with HER2-overexpressing breast, gastric and gastroesophageal junction cancers.

The underlying NK cell is derived from umbilical cord blood donors preselected for advantageous attributes including the high affinity variant of the CD16 receptor and a KIR-B haplotype. AB-201 cell products maintain high expression of CD16, as well as other activating innate cell tumor engaging receptors, enabling the potential for dual targeting therapeutic approaches via monoclonal antibody combinations. The resulting CAR NK is manufactured at very large scale and cryopreserved in infusion-ready media to enable repeat clinical administrations in the outpatient setting.

Kite

Kite, a Gilead Company (CA, USA; www.gilead.com), has announced that the US FDA has approved a manufacturing process change resulting in a shorter manufacturing time for Yescarta^® (axicabtagene ciloleucel). With this approval, Kite's median turnaround time (TAT) in the US is anticipated to be reduced from 16 days to 14 days [34].

Median TAT is defined as time from leukapheresis, when a patient's T cells are collected, to product release; manufacturing is a key step within this process to prepare a patient's cells for a one-time cell therapy infusion customized for each patient.

Kyverna

Kyverna Therapeutics (CA, USA; www.kyvernatx.com), a clinical-stage biopharmaceutical company focused on developing cell therapies for patients suffering from autoimmune diseases, announced the clearance of its IND application by the US FDA for its autologous, fully human CD19 CAR T cell product candidate, KYV-101, to be used for the treatment of multiple sclerosis. Kyverna's CD19 CAR T-cell therapy, KYV-101, specifically targets CD19, a protein expressed on the surface of B cells, which is involved in various types of autoimmune diseases [35].

Shortly after, the company has received also fast track designation from the US FDA for KYV-101 to be used for the treatment of multiple sclerosis [36].

NK CellTech

NK CellTech (China; www.nk-celltech.com) a company focused on the development of NK cellular therapies, has announced that the FDA has granted clearance for the clinical trial of NK010, the non-genetically modified natural killer cells. NK010 is the first non-genetically modified NK cells expended from allogeneic peripheral blood cell (PBMC) approved for clinical trial by the FDA from China [37].

NK010 exhibits multiple high anti-tumor advantages including wide spectrum and high expression of NK cell activation receptors and high purity, which makes it possible to treat variety types of tumors. NK010 also shows the potential to treat non-tumor diseases and can be the best basal cell for a subsequent series of synthetic NK cell drugs (SynNK) developed by the company. The ovarian cancer was the first indication chosen for exploration in this Phase I clinical trial. Pre-clinical studies have shown outstanding potential, with NK010 exhibiting strong tumor growth inhibition on ovarian cancers in animal models, liver cancer and other solid tumors as well as acute myeloid leukemia.

Oricell

Oricell Therapeutics (China; www.oricell.com), a clinical-stage biotechnology company, has announced that the US FDA has cleared the company's IND application for OriCAR-017 for patients with relapsed/refractory multiple myeloma [38]. OriCAR-017 is a CAR T cell therapy targeting GPRC5D. The therapy leverages Oricell's proprietary platforms including Ori^®Ab antibodies, Ori^®CAR construct and unique know-how to achieve optimal binding and superior persistence and anti-tumor efficacy out of rejuvenated CAR-T cells. The IND enables Oricell to initiate the clinical development for OriCAR-017 in the US immediately. The FDA IND approval for OriCAR-017 follows its NMPA IND approval in 2023.

Vertex

Vertex Pharmaceuticals (MA, USA; www.vrtx.com) has announced that the Saudi Food and Drug Authority (SFDA) granted Marketing Authorization for CASGEVY™ (exagamglogene autotemcel [exa-cel]), a CRISPR/Cas9 gene-edited therapy, for the treatment of sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT) [39].

A few days later, US FDA has also approved CASGEVY for the treatment of TDT in patients 12 years and older [40].

Acquisitions

STEMCELL Technologies & Propagenix

STEMCELL Technologies (Canada; www.stemcell.com) has announced the acquisition of Propagenix (MD, USA; https://propagenix.com) [41]. Founded in 2014, Propagenix has developed and commercialized unique technologies, including its patented EpiX™ technology. In 2017, STEMCELL licensed the rights to EpiX for research use applications. This technology has the potential to address clinical needs in replacing a patient's own damaged barrier tissues, like skin and intestinal tissue, with engineered tissue solutions. The current acquisition now enables STEMCELL to develop products based on EpiX technology for clinical applications.

Capital market & finances

Adicet Bio

Adicet Bio (MA, USA; www.adicetbio.com), a clinical stage biotechnology company discovering and developing allogeneic gamma delta T cell therapies for autoimmune diseases and cancer, has closed underwritten public offering of 32,379,667 shares of its common stock [42]. The shares of common stock were sold at a public offering price of US$2.40 per share. The aggregate gross proceeds from the offering, before deducting underwriting discounts and commissions and offering expenses, were approximately US$98.0 million. All of the securities in the offering were sold by Adicet.

Legend & Novartis

Legend Biotech (NJ, USA; https://legendbiotech.com), a global biotechnology company developing, manufacturing and commercializing novel therapies to treat life-threatening diseases, closed its previously announced exclusive, worldwide license agreement with Novartis Pharma (Switzerland; www.novartis.com) for certain Legend Biotech CAR T cell therapies targeting DLL3, including Legend Biotech's existing autologous CAR-T cell therapy candidate, LB2102 [43,44]. Under the terms of the license agreement, Legend Biotech will receive a US$100 million upfront cash payment.

Moonwalk

Moonwalk Biosciences (CA, USA; https://moonwalk.bio), a genomic medicine company pioneering precision epigenetic medicines, has completed US$57 million in seed and Series A financing [45]. The financing will support continued advancement of Moonwalk's epigenetic profiling and engineering technology platform and progress its pipeline of epigenetic therapeutics toward the clinic.

By targeting the epigenetic code – the software of the genome – Moonwalk aims to reprogram cells to their healthy state, fundamentally enabling a new approach to how therapies are discovered and developed. Moonwalk is the first company that couples an epigenetic discovery platform with precise engineering – opening up the epigenome as a new target space for complex diseases. Moonwalk's focus on epigenetic engineering leverages comprehensive read-and-write technologies to develop potentially curative therapies for a variety of different diseases at the root cause level.

Tr1X

Tr1X (CA, USA; www.tr1x.bio). has announced its emergence from stealth with a US$75 million Series A financing to bring universal allogeneic regulatory T (Treg) and CAR-Treg cell therapies to the clinic to treat and potentially cure autoimmune and inflammatory diseases [46]. Tr1X's proprietary technology enables the conversion of CD4 T cells isolated from healthy donors into Treg-like cells that have a similar function and profile to naturally occurring Tr1 cells. These cells can be further engineered to target specific tissues or organs to enable local, targeted immunomodulation. With a proprietary, GMP-grade, closed-loop system that provides consistency, quality and reliability at scale, Tr1X can enable production of its products at commercial volume.

Currently, Tr1X is working on its first investigational Tr1 cell therapy, TRX103, which it plans to evaluate in a phase I trial to prevent graft versus host disease in patients undergoing mismatched hematopoietic stem cell transplant. The company is developing additional pipeline programs to treat inflammatory bowel disease, Type I diabetes and multiple B-cell-mediated autoimmune diseases.