B7-H4, a member of the B7 family of immune modulators, negatively regulates both T cell immune responses and anti-tumor immunity. While B7-H4 is highly expressed in a range of solid tumors, expression in heathy tissues is limited. Hence, we sought to generate a therapeutic antibody that both blocks the T cell inhibitory checkpoint activity of B7-H4 and mediates potent antibody-dependent cell-mediated cytotoxicity (ADCC) against B7-H4-expressing tumor cells.
Fully human B7-H4 antibodies raised by screening Adimab’s yeast-based platform were evaluated for protein and cell binding, epitope specificity, and species cross-reactivity. We assessed these B7-H4 antibodies for checkpoint blockade activity using our proprietary in vitro assay, comprised of primary human T cells and B7-H4-expressing artificial antigen presenting cells. We used primary human cell-based and reporter cell line-based assays to assess the in vitro ADCC activity of B7-H4 antibodies against B7-H4-expressing target cell lines. We assessed the in vivo anti-tumor efficacy of our lead B7-H4 antibody in mice bearing syngeneic tumor cell lines engineered to display mouse B7-H4.
After generating a panel of B7-H4 antibodies, we found that 12 out of 41 antibodies reverse B7-H4-mediated inhibition of T cell proliferation and IFNg production in vitro. Importantly, 11 of these antibodies with checkpoint blockade activity belong to the same epitope bin, recognize the B7-H4 IgV domain, and fully cross-react with cynomolgus monkey and rodent B7-H4, suggesting that these antibodies bind and block an evolutionarily conserved functional domain. When glycoengineered for enhanced FcgRIIIa binding, selected checkpoint blockade antibodies also mediate potent ADCC activity against cells exhibiting a range of B7-H4 expression. In a murine tumor model expressing B7-H4, our selected therapeutic candidate FPA150 significantly impairs tumor growth in a dose-dependent manner.
We generated a therapeutic candidate B7-H4 antibody, FPA150, which possesses both T cell immune checkpoint blockade and ADCC activity. We initiated IND-enabling studies and plan to file an IND application by the end of 2017.
Clinical trial identification
Legal entity responsible for the study
Five Prime Therapeutics
Five Prime Therapeutics
C.D. Kaplan: Currently employed by and own stock in Five Prime Therapeutics. D. Houser, A. Hsu, K. Legris, G. Brattich, H. Xiang, A. Ahene, U. Jeffry, D. Bellovin, L. Borges, F. Kemp: Currently employed by Five Prime Therapeutics N. Nielson: Currently employed by Adimab.