A Novel B7-H6-targeted IgG-like T-cell Engaging Antibody for the Treatment of Gastrointestinal Tumors

Abstract Purpose: Advanced stage gastrointestinal cancers represent a high unmet need requiring new effective therapies. We investigated the anti-tumor activity of a novel T-cell engaging antibody (B7-H6/CD3 ITE) targeting B7-H6, a tumor-associated antigen that is expressed in gastrointestinal tumors. Experimental Design: Membrane proteomics and immunohistochemistry analysis identified B7-H6 as tumor- associated antigen in gastrointestinal tumor tissues with no to very little expression in normal tissues. The anti-tumor activity and mode of action of B7-H6/CD3 ITE was evaluated in in vitro co-culture assays, in humanized mouse tumor models, and in Colorectal Cancer Precision Cut Tumor Slice Cultures. Results: B7-H6 expression was detected in 98 % of colorectal, 77 % of gastric cancer, and 63 % of pancreatic cancer tissue samples. B7-H6/CD3 ITE-mediated redirection of T cells towards B7-H6-positive tumor cells resulted in B7-H6-dependent lysis of tumor cells, activation and proliferation of T cells, and cytokine secretion in in vitro co-culture assays, and infiltration of T cells into tumor tissues associated with tumor regression in in vivo CRC models. In primary patient-derived Colorectal Cancer Precision Cut Tumor Slice Cultures, treatment with B7-H6/CD3 ITE elicited cytokine secretion by endogenous tumor infiltrating immune cells. Combination with anti-PD-1 further enhanced the activity of the B7-H6/CD3 ITE. Conclusions: These data highlight the potential of the B7-H6/CD3 ITE to induce T-cell re-directed lysis of tumor cells and recruitment of T cells into non-inflamed tumor tissues leading to anti-tumor activity in in vitro, in vivo, and human tumor slice cultures which supports further evaluation in a clinical study.