Combination therapy with a novel CD2-targeted costimulatory bispecific antibody overcomes limitations of CD3 T cell engager treatment for solid tumors.

CD3 T cell engagers (TCEs) have transformed hematologic oncology, but dose-liming toxicity and the absence of adequate costimulation have limited TCE success in solid tumors. Consequently, to date, only one classical TCE developed for solid tumors - tarlatamab - has been granted a marketing approval. Here, we report a pioneer combination strategy using a novel CD2-targeted costimulatory bispecific antibody to overcome these limitations. Building on a unique non-blocking CD2 antibody, we developed a HER2×CD2 proof-of-concept bispecific that, combined with an EpCAM×CD3 TCE, provides tumor-dependent costimulation and enhances anti-tumor cytotoxicity mediated by the TCE. We show that HER2×CD2 can be dosed independently to restore optimal anti-tumor cytotoxicity of a sub-efficacious low dose of the EpCAM×CD3 TCE, thus providing a route to avoid TCE-driven toxicity while maintaining efficacy. In a humanized xenograft model, co-treatment with HER2×CD2 achieved complete tumor remission in 8 of 9 mice at a TCE dose that otherwise mediated complete remission in only 1 of 9 mice. We show that HER2×CD2 compensates for the loss of CD58 expression by tumor cells - a well-documented tumor escape mechanism. Notably, unlike CD28-based costimulation, HER2×CD2 effectively also harnessed the anti-tumor cytotoxicity of CD28-negative CD8 T cells - a potent cytotoxic subset prevalent in elderly patients and dominant in solid tumors. Furthermore, HER2×CD2 induced markedly lower cytokine release than a HER2×CD28 bispecific while mediating comparable improvement in anti-tumor cytotoxicity. These findings establish our novel CD2-targeted costimulatory bispecific antibody approach as a promising and potentially safe way to expand and enhance TCE immunotherapy for solid tumors.