Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Autoimmune disorders, Hodgkin lymphoma, Antibody Therapy, Lymphomas, Non-Hodgkin lymphoma, Drug development, Bispecific Antibody Therapy, B Cell lymphoma, Diseases, Immune Disorders, Aggressive lymphoma, Treatment Considerations, Biological therapies, Immunotherapy, Immunology, Lymphoid Malignancies, Biological Processes
Methods: Here we report on the development of a next-generation 2:1 format EVOLVE with integrated CD2-costimulation to improve CD3-mediated T cell receptor activation and sustain T cell-mediated cytotoxicity by increasing avidity-driven binding and the potential for the formation of alternative tumor-T cell synapses, to achieve potential superior performance to clinical benchmarks.
Results: EVOLVE205 with 2:1 molecular format and integrated CD2-costimulatory agonist shows superior cytotoxicity in both high (WSU-DLCL2)and low CD20 (HT) expressing diffuse large B-cell lymphoma cell lines. In an in vitro co-culture assay with HT tumor cells and human PBMCs, EVOLVE205 displays improved human T cell activation, increased T cell expansion, and superior tumor cell killing without a substantial increase in cytokine release compared to 1:1 and 2:1 CD20-targeted clinical benchmark bispecifics. Importantly, in a B-cell depleted PBMC-HT tumor co-culture assay, the tumor-killing potency of EVOLVE205 was improved by up to 60-fold compared to Glofitamab and Epcoritamab, and by over 1,000-fold compared to B-cell depleting therapeutics (BCDTs) such as Rituximab. These data suggest the potential for EVOLVE205 to establish an improved therapeutic index relative to these clinical benchmarks. In a PBMC-engrafted xenograft NSG mouse model with CD20high WSU-DLCL2 cell line, EVOLVE205 showed significant tumor growth inhibition efficacy comparable to Glofitamab.
Conclusion: CD20-targeted EVOLVE205 utilizes integrated CD2 costimulation to potently induce T cell activation and tumor killing without mediating significant cytokine release, and demonstrates significant in vivo efficacy, IgG-like pharmacokinetics, and a favorable developability profile. These features of EVOLVE205 appear to offer efficacy and safety advantages compared to clinically available CD20-targeted TCE therapies and BCDTs for the treatment of B cell lymphomas and for B cell-mediated autoimmune diseases.
Disclosures: An: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Sarkar: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Jin: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Liang: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Lichter: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Klaskin: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Sabrin: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Teran: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Abdukadir: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Karp: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Rodriguez: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Capiralla: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Lai: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Preyer: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Matis: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Martomo: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Meade: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Fine: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company. Myers: EvolveImmune Therapeutics, Inc.: Current Employment, Current equity holder in private company.
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