Abstract 2137: EVOLVE205, a dual (2:1) CD20 targeted CD3 trispecific T cell engager with CD2 costimulation for the treatment of B cell malignancies and B cell autoimmune disorders

Abstract T cell engager (TCE) CD3-bispecifics have improved the treatment of patients with B cell lymphomas leading to recent approvals of the CD20-targeted CD3 bispecifics including Glofitamab, Mosunetuzumab, and Epcoritamab for patients with relapsed, refractory diseases. Recently, combinations of CD3-bispecifics and tumor-targeted costimulatory agonists have demonstrated enhanced efficacy in preclinical models. These combination approaches are currently being investigated in the clinic but may have challenges in establishing optimal dose scheduling and dose levels to ensure simultaneous CD3 and costimulatory pathway activation. T cell costimulation using CD2 is an alternative strategy that may provide significant benefits compared to 4-1BB and CD28 due to sustained CD2 surface expression on T cells found in the tumor microenvironment. EVOLVE205 molecules are dual (2:1) CD20-targeting TCE with integrated CD2 agonism to redirect optimized T cell effector function through CD2 co-stimulation, increasing avidity-driven binding to CD20, to achieve potential superior performance to clinical benchmarks. EVOLVE205 molecules show superior cytotoxicity in diffuse large B-cell lymphoma cell line models and primary tissue B cells. In a PBMC-HT (CD20low) co-culture assay, EVOLVE205 displays improved 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 70-fold compared to Glofitamab, and by over 1, 000-fold compared to anti-CD20 mAbs such as Rituximab. EVOLVE205 also demonstrated superiority in depleting primary tissue B cells over approved CD20 or CD19 targeting clinical benchmarks. 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 significantly enhanced tumor growth inhibition efficacy at the tumor growth permissible dosing level of Glofitamab. CD20-targeted EVOLVE205 shows high tumor-killing potency without inducing exaggerated cytokine production in vitro. It also demonstrates significant in vivo efficacy and a favorable developability profile. Our data indicated that EVOLVE205 with integrated CD2 co-stimulation offers greater efficacy and safety advantages compared to clinically available CD20-targeted TCE therapies and anti-CD20 mAbs for the treatment of B cell lymphomas and for B cell-mediated autoimmune diseases. Citation Format: Xingyue An, Mohosin Sarkar, Guixian Jin, Tiffany Liang, Afsana Sabrin, Tracy Lichter, Danielle Klaskin, Evelyn Teran, Abliz Abduqadir, Hayden Karp, Julio Rodriguez, Hemachander Capiralla, Zengzu Lai, Louis Matis, Stella Martomo, Agnes Meade, Martin Preyer, Jay S. Fine, Jeremy S. Myers. EVOLVE205, a dual (2:1) CD20 targeted CD3 trispecific T cell engager with CD2 costimulation for the treatment of B cell malignancies and B cell autoimmune disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2137.