PLEASANTON, Calif. & NANJING, China & SHANGHAI, August 18, 2021–(BUSINESS WIRE)–IASO Biotherapeutics (IASO Bio), a clinical-stage biopharmaceutical company advancing the development of novel cell therapies for cancer, today announced that the preclinical results of the company’s proprietary next-generation chimeric antigen receptor (CAR)-T cell therapy, CT125A, were recently published in Molecular Therapy, an internationally renowned peer-reviewed scientific journal. CT125A is a novel first-in-class CAR-T therapy and a groundbreaking asset developed on IASO Bio’s fully human antibody platform IMARS for the treatment of T cell hematologic malignancies.
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Screenshot of IASO Bio’s published preclinical results (source: cell.com) (Graphic: Business Wire)
Molecular Therapy is the official periodical of the American Society of Gene & Cell Therapy, and is published under Cell. With an impact factor of 11.454 in 2021, Molecular Therapy is dedicated to publishing peer-reviewed and cutting-edge reviews and commentaries, for promoting the sciences in genetics, medicine, and biotechnology. The published study was jointly carried out by IASO Bio and the research team led by Prof. Jianfeng Zhou at Tongji Hospital of Huazhong University of Science and Technology’s Tongji Medical School. Dr. Zhenyu Dai and Dr. Wei Mu of IASO Bio are the co-first authors of the paper, and Dr. Taochao Tan, Executive Director of R&D at IASO Bio, is the program lead in charge of the preclinical development of CT125A.
Study highlight: a new strategy for treatment of T cell malignancies
Researchers of the study successfully selected CD5-targeting fully human heavy-chain variable (FHVH) domains from a phage display library, and knocked out CD5 from those T cells using CRISPR/Cas9 technology, overcoming self-activation and fratricide problems on CAR-T cells. A series of in vivo and in vitro functional comparisons validated the hypothesis that tandem VH domains targeting different epitopes could potentially enhance the function of CAR-T cells, and CT125A, with its biepitopic FHVH3/VH1 CAR-T cells, offers a promising new strategy for the treatment of T cell malignancies.
CD5: a novel and safe target for the treatment of T cell malignancies
In recent years, CAR-T technology has seen numerous breakthroughs and achieved tremendous progress with the development of targets for the treatment B cell malignancies. However, the research and application of CAR-T technology in the treatment of T cell malignancies thus far remains limited. T cell malignancies include T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphoma (TCL)1. CD5 overexpression occurs in approximately 85% of all T cell malignancies, while CD5 expression in normal human cells only occurs in thymocytes, T cells, and B1 cells. CD5 is also expressed in certain B cell malignancies, making CD5 a valid target for the treatment of both T cell and B cell malignancies. At present, only a handful of CD5-targeting therapies are in development, and all of these programs are at early stages.
A groundbreaking biepitopic: CAR-T with fully human heavy-chain-only binding domains offers more potent and durable antitumor activity with lower immunogenicity. The study used IASO Bio’s in-house developed fully human phage display antibody library IMARS to generate antibodies that specifically bind to the CD5 antigen (including scFv and VH only domains), developed CAR-T cells using CD5-specific antibodies, and subsequently compared the function of candidate CAR molecules. To eliminate the adverse effects of fratricide on CAR-T cells, researchers performed CRISPR/Cas9-based CD5 knockout on the T cells, and further developed and optimized the cell-generating process that delivered the high CD5 knockout efficiency and high-quality generation of CAR-T cells. Based on this process, researchers generated clones that exhibited both superior antitumor activity and significantly higher proliferation than the control CAR (H65) in vivo.
Through a competitive analysis, researchers identified FHVH1 and FHVH3 domains that specifically bind to different epitopes of CD5. To further enhance the function of CAR-T cells and minimize the risk of tumor escape due to the mutation and down-regulated expression of the CD5 antigen, researchers further developed and optimized the structural arrangement of tandem VH CARs. Compared to FHVH1, FHVH3, and H65 CAR-T controls, biepitopic FHVH3/VH1 CAR-T cells demonstrated higher levels of degranulation and cytotoxicity in CD5+ cells, including the cell lines with relatively low levels of CD5 expression. In murine-derived tumor models, biepitopic FHVH3/VH1 CAR-T cells cleared T-ALL cells earlier than FHVH1 and FHVH3 CAR-T cells and maintained a longer remission than FHVH1 and FHVH3 CAR-T cells. This finding indicates the more potent and durable antitumor activity of biepitopic FHVH3/VH1 CAR-T cells.
CT125A: a promising new therapy that could bring hope to patients with T cell malignancies
Compared to patients with B cell malignancies, those with T cell malignancies treated with radiochemotherapies have a higher rate of relapse and poorer prognoses, thus representing an urgent unmet clinical need. CT125A is an innovative first-in-class CAR-T therapy that could potentially bring hope to patients with relapsed/refractory T cell malignancies. Furthermore, CD5 is also commonly overexpressed in some hard-to-treat B cell malignancies such as B cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL), suggesting therapeutic utility in an even broader spectrum of hematologic indications.
“Due to the high relapse rates and dismal prognoses after radiochemotherapies, T cell malignancies remain a hard-to-treat subtype of hematologic malignancies with an urgent need for effective treatment options,” said Dr. Biao Zheng, Chief Scientific Officer of IASO Bio. “CT125A is developed using a gene editing technology that delivers CD5 knockout in T cells to prevent the self-activation and fratricide of CAR-T cells. It also leverages CD5-targeting fully human heavy-chain-only binding domains that regulate the development of antibodies. Thus, CT125A can effectively address the high relapse rate of T cell malignancies caused by the lack of in vivo persistence of CD5-targeting CAR-T cells.”
Results from this study showed that CD5-targeting CAR-T cells are safe and have potent clinical activity in patients with r/r CD5+ T-ALL or T cell non-Hodgkin lymphoma (T-NHL), and could potentially allow patients who are ineligible for transplants to finally receive hematopoietic stem cell transplantation (HSCT). As CD5 is also commonly overexpressed in certain B cell malignancies, this CAR-T candidate also has clinical utility in patients with B cell malignancies such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Furthermore, the application of CAR-T therapy to target two or more antigens simultaneously is an attractive strategy for treatment and prevention of antigen-loss relapses. Using two VH domains can simplify the design of bispecific CAR constructs, and is therefore an effective approach to solving critical problems in cancer drug development, such as clonal heterogeneity and antigen escape.
CT125A is currently undergoing chemistry, manufacturing, and control (CMC) studies, as well as an investigator initiated clinical trial (ClinicalTrials.gov identifier: NCT04767308).
About IASO Bio
IASO Bio is a clinical-stage biopharmaceutical company engaged in the discovery and development of novel cell therapies for oncology and autoimmune diseases. Leveraging its proprietary fully human antibody discovery platform (IMARS), high-throughput CAR-T drug priority platform, and proprietary manufacturing processes, IASO Bio is developing a rich clinical-stage pipeline of multiple autologous and allogeneic CAR-T and biologics product candidates. Currently, the company is developing a diversified portfolio of over 10 novel pipeline products. IASO’s leading asset, CT103A, an innovative anti-BCMA CAR-T cell therapy under pivotal study for relapsed/refractory (R/R) multiple myeloma (RRMM), was granted Breakthrough Therapeutic Designation by China’s National Medical Products Administration (NMPA) in February 2021. For more information, please visit www.iasobio.com.
1. Alcantara M, Tesio M, June CH, Houot R. CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells. Leukemia. 2018;32(11):2307-15.
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