IASO Biotherapeutics Publishes Preclinical Results of Its CD5-Targeting CAR-T in Molecular Therapy
PLEASONTON, CALIF., NANJING, and SHANGHAI, August 12, 2021 - IASO Biotherapeutics (IASO Bio) announced that the preclinical results of the company’s proprietary next-generation chimeric antigen receptor (CAR)-T cell therapy, CT125A, were recently published in the internationally renowned scientific journal Molecular Therapy. 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.
A screenshot of the published paper (source: cell.com)
Molecular Therapy, the official periodical of the American Society of Gene & Cell Therapy, is published under Cell, one of the world’s most renowned scientific journals. 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 Tongji Medical School of Huazhong University of Science and Technology. 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.
Highlight of the study: a new strategy for the 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 the CRISPR/Cas9 technology, overcoming the problems of self-activation and fratricide on the 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 amount of research and application of CAR-T technology in the treatment of T cell malignancies thus far remain limited. T cell malignancies include acute 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 the CD5 expression in normal human cells only occurs in thymocytes, T cells, and B1 cells. Meanwhile, 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.
CT125A is a groundbreaking biepitopic CAR-T with fully human heavy-chain-only binding domains offering more potent and durable antitumor activity with lower immunogenicity. This study used IASO Bio’s in-house developed fully human phage display antibody library IMARS to generate antibodies specifically bind to 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, 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 optimized 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 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, thereby indicating the more potent and durable antitumor activity of biepitopic FHVH3/VH1 CAR-T cells.
Phage display library screening and selection of fully human (FH) CD5-specific, heavy-chain variable domain (VH)
(A) Schematic of the CD5-specific VH discovery process. (B) Binding activities of representative phage clones and KO7 (negative control phage) are shown. Binding to different antigens was detected after staining with mouse anti-M13 antibody and horseradish peroxidase (HRP)-goat anti-mouse IgG antibody before reading the optical density at 450 nm. Mouse anti-CD5 and HRP-goat anti-mouse IgG antibodies were used as the positive control. (C) Phage clones FHVH1–4 bind to Jurkat and CCRF-CEM (both CD5+) cells, but not to Raji and K562 (both CD5-) cells. Shown is analyzed using flow cytometry.
The in vivo antitumor activity of CD5-targeting CAR-T cells in the tumor model established by SUP-T1.
(A) Mouse tumor burden of each treatment group at the indicated time points. The results are displayed as mean ± SEM (n = 6). (B) Growth and staging of the tumor monitored by bioluminescence imaging are shown.
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 prognosis, 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.
Dr. Biao Zheng, Chief Scientific Officer of IASO Bio, commented: “Due to the high relapse rate and dismal prognosis after radiochemotherapies, T cell malignancies remain a hard-to-treat subtype of hematologic malignancies with an urgent need for effective treatment options. CT125A is developed using a gene editing technology that delivers the CD5 knockout in T cells to prevent the self-activation and fratricide of CAR-T cells; and leverages CD5-targeting fully human heavy-chain-only binding domains that regulate the development of antibodies. Thereby, CT125A can effectively address the high relapse rate 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 to 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 MCL and 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. The use of two VH domains can simplify the design of bispecific CAR constructs, therefore is an effective approach to solve critical problems in current cancer drug development, such as clonal heterogeneity and antigen escape.”
CT125A is currently undergoing chemistry, manufacturing, and control (CMC) studies and an investigator initiated clinical trial (ClinicalTrials.gov identifier: NCT04767308).
Reference
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.
