Sergeeva and Jin et al. developed the EVOLVE trispecific T cell engager (TCE) platform, comprising a tumor antigen-targeting domain, an affinity-attenuated CD3 agonist (optimized to increase T cell viability and effector function), and an LFA-3 extracellular domain fragment (to induce CD2 costimulation) in an IgG1 format, with Fc chain effector-inactivating mutations. EVOLVE TCEs exhibited greater tumor-killing potency than CD3 affinity-matched bispecifics in vitro, and induced greater, more durable antitumor activity and lower tumor antigen-dependent cytokine release than control (higher and lower affinity) CD3 TCEs in mouse xenograft models.
Contributed by Paula Hochman
ABSTRACT: Ten CD3 T cell engagers (TCEs) have received regulatory approval for the treatment of hematologic and solid tumors. However, limited costimulatory signaling essential for sustained T cell effector activity may limit CD3 TCE clinical efficacy and response duration. The CD2 receptor is an attractive costimulation target owing to its association with T cell receptor signaling and favorable expression profile. We show that CD2 costimulation is superior in maintaining T cell viability and effector function relative to other pathways in in vitro chronic stimulation assays. The extracellular domain of CD58, the predominant CD2 ligand, is functional as an antibody fusion, improving bispecific potency. We observe that higher CD3 affinity molecules have the potential for superagonism in the context of an integrated CD2 agonist. Evaluation of TCEs with integrated CD2 costimulation and attenuated CD3 binding identified optimal CD3 affinity agonists that avoid target-independent T cell activation and demonstrated an increased therapeutic index relative to nonattenuated CD3 agonists. This platform shows increased tumor-killing efficacy as compared to CD3 affinity-matched bispecifics for known tumor targets such as HER2, CD20, B7-H4, and UL16-binding protein 2 (ULBP2). We demonstrate that ULBP2-targeted trispecifics with integrated CD2 costimulation and optimized CD3 affinity are superior to higher-affinity CD3 molecules in in vivo mouse efficacy studies. This integrated CD2 costimulation platform, which we termed EVOLVE, represents a next-generation TCE platform to increase T cell effector function in the tumor microenvironment and has the potential to address unmet patient needs by improving the depth and durability of clinical antitumor T cell responses.
Author Info: (1) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (2) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (3) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (4) Evolv
Author Info: (1) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (2) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (3) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (4) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (5) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (6) EvolveImmune Therapeutics, Inc., Branford, CT 06405. Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591. (7) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (8) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (9) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (10) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (11) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (12) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (13) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (14) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (15) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (16) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (17) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (18) Independent Consultant, Kensington, CA 94708. (19) EvolveImmune Therapeutics, Inc., Branford, CT 06405. Antibody Technology Fred Hutchinson Cancer Center, Seattle, WA 98109. (20) NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037. (21) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (22) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (23) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (24) EvolveImmune Therapeutics, Inc., Branford, CT 06405. (25) EvolveImmune Therapeutics, Inc., Branford, CT 06405.
