Abstract 2369: EVOLVE-105, a differentiated CD20-targeted CD2 co-stimulatory T cell engager engineered for the treatment of B cell malignancies

Abstract

Abstract Despite the recent approvals of CD20-targeted CD3 bispecific molecules in follicular lymphoma (Lunsumio™, mosunetuzumab) and diffuse large B cell lymphoma (Columvi™, glofitamab; and Epkinly™, epcoritamab), significant opportunities to improve patient outcomes in these indications remain. Targeted induction of T cell costimulatory receptors (signal 2) as a complement to T cell activation mediated by T cell receptor signal 1 is an attractive strategy to sustain and optimize the redirected T cell effector response to these tumors. Drug combinations of CD3-bispecifics and tumor-targeted costimulatory biologics such as CD19-41BBL and CD19-CD28 costimulatory agonists are promising approaches that have shown preclinical efficacy and are being investigated in the clinic. EVOLVE-105 is a CD20-targeted trispecific T cell engager biotherapeutic with an integrated, affinity-tuned CD3 and a CD2 co-stimulatory agonist. The advantages of physical integration include an increased probability of simultaneous T cell receptor and CD2 receptor engagement on each T cell and a simplified patient management strategy, compared to drug combinations of molecules individually targeting each receptor. EVOLVE-105 displays improved human T cell activation, increased T cell expansion, and tumor cell killing activity without a substantial increase in cytokine release compared to CD20xCD3 bispecifics with matching CD3 affinity which does not supply CD2 costimulation. EVOLVE-105 also displays superior potency compared to the CD20xCD3 clinical benchmarks mosunetuzumab, epcoritamab, and odronextamab. Importantly, the tumor-killing potency of EVOLVE-105 was within two-fold of the activity of glofitamab, while inducing less cytokine release, suggesting its potential to establish an improved therapeutic index. In cynomolgus monkeys, EVOLVE-105 demonstrated favorable tolerability and pharmacokinetics consistent with an attractive clinical developability profile. Sustained, dose-dependent B cell depletion in peripheral blood, lymph nodes, and spleen was observed. Circulating cytokine excursions, including IL-6, IFNγ, and TNFα at efficacious doses were markedly reduced by EVOLVE-105 treatment, in contrast to the circulating levels of cytokines reported for epcoritamab and glofitamab at their efficacious doses. EVOLVE-105 demonstrates favorable biophysical properties conducive to its development as intravenous and subcutaneous formulations. The emerging profile of EVOLVE-105 suggests its potential as a differentiated CD20-targeted immunotherapy capable of providing superior, more durable tumor control with a preferred cytokine release profile, compared to current CD20-targeted T cell engager therapies. Citation Format: Xingyue An, Mohosin Sarkar, Stella Martomo, Maria Hackett, Guixian Jin, Tiffany Liang, Danielle Klaskin, Tracy Lichter, Nana Adjoa Pels, Abudukadier Abulizi, Evelyn Teran, Afsana Sabrin, Oksana A. Sergeeva, Amber Fearnley, Hayden Karp, Julio Rodriguez, Eric M. Tam, Louis Matis, Jay S. Fine, Jeremy S. Myers. EVOLVE-105, a differentiated CD20-targeted CD2 co-stimulatory T cell engager engineered for the treatment of B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2369.