A conditionally-active, dual-targeting BiTAC-TCE with superior tumor selectivity for the treatment of solid tumors

The broad application of T cell engagers (TCEs) in solid tumors is limited by on-target, off-tumor toxicity. Our proprietary BiTAC-TCE platform combines dual-targeting with on-cell assembly of two complementary molecules. Each molecule contains a tumor-binding domain, recognizing a unique tumor-associated antigen (TAA), and a split T cell–binding moiety. Productive T cell engagement occurs when both compounds bind tumor cells expressing both antigens which triggers the complementation of the CD3 binder. For ourlead program, we combine EpCAM with another clinically validated TAA that has a distinct expression pattern in healthy tissue. The combination of EpCAM and TAA2 enables the safe targeting of major solid tumor indications known to highly co-express both targets, e.g. CRC or NSCLC. Our lead BiTAC-TCE molecules have a favorable developability and PK profile. BiTAC-TCE discriminates between dual (tumor) and single expressing (healthy surrogate) cells and spheroids in vitro, demonstrating its implemented logic AND-gate function. The combination induces strong efficacy in a CRC-derived CDX model. As opposed to an EpCAM-targeting TCE, our BiTAC-TCE does not show any signs of toxicity in a transgenic mouse model expressing the human version of EpCAM. Collectively, these data demonstrate the BiTAC-TCE platform may be able to provide safe and efficacious treatment options for solid tumor indications with high unmet medical need.