Abstract 3501: A novel CD2-targeted costimulatory bispecific antibody platform for enhancing CD3 T cell engager-based cancer immunotherapy

Abstract CD3-based T cell engagers (TCEs) are a clinically successful class of bispecific antibodies that has delivered 11 approved agents to date, albeit primarily for treatment of blood cancers. These agents provide a strong signal 1 for redirecting polyclonal T cells, regardless of their native specificity, to kill cancer cells. However, when only receiving signal 1 for prolonged periods of time without a costimulatory signal, T cells become anergic and exhausted. In part due to the lack of costimulatory signals in the tumor microenvironment, TCEs have had limited therapeutic success in solid tumor indications so far. Interestingly, single cell RNA sequencing data from multiple solid tumor types revealed that a high percentage of tumor infiltrating T cells express high levels of CD2 but not CD28 or other costimulatory receptors. Based on a proprietary antibody that binds a unique epitope on the costimulatory T cell receptor CD2, we have developed a novel bispecific antibody platform (BiTco) that provides costimulation to T cells via CD2 in the context of a tumor-associated antigen. Using primary human T cells as effectors in vitro, we found that CD2 and CD28 costimulation potentiated T cell activation and T cell-mediated tumor cell killing to a comparable extent. However, the CD2 BiTco format triggered less pronounced cytokine release making it a potentially safer clinical option. Moreover, we demonstrated that, unlike CD28, our CD2 BiTco format also provides robust costimulation to CD28-negative CD8 T cells that possess high cytotoxic capacity and constitute the majority of CD8 T cells found in elder patients. Further, by using a fixed sub-efficacious dose of CD3 TCE we simulated in vitro a clinical setting where reduced expression of tumor antigen can result in loss of CD3 TCE monotherapy efficacy. When adding increasing doses of CD2 BiTco in this setting we could fully restore optimal anti-tumor cytotoxicity and T cell activation. In addition, we knocked out CD58 on tumor target cells to mimic loss of expression of this primary ligand of CD2, which is another known mechanism of immune escape by tumors. We showed that BiTco treatment allows to recover and even enhance TCE-mediated T cell cytotoxicity in the absence of tumor-expressed CD58. Finally, we established a BT474 clone 5 xenograft model using immunodeficient mice, in which a human T cell compartment was reconstituted by injection of human PBMCs. In this in vivo model we showed that combination treatment of CD2 BiTco with a sub-efficacious dose of a CD3 TCE resulted in highly effective control of tumor growth by human T cells. In summary, combination therapy with our differentiated CD2 BiTco platform can improve CD3 TCE response and limit acquired resistance mediated by loss of tumor antigen and/or CD58. Citation Format: Gerhard J. Niederfellner, Welbeck Danquah, Melanie Pichery, Thomas Eden, Aurelien Boyance, Lise Pasquet, Virginie Roure, Alice Marchand, Marion Mars, Ellen Gumz, Mylene Gador, Lou Valente, Marion Contini, Lukas Czernecki, Sanjit Shanmuganathan, Markus Dangl. A novel CD2-targeted costimulatory bispecific antibody platform for enhancing CD3 T cell engager-based cancer immunotherapy [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 3501.