Development And Functional Characterization Of Nc762, A Novel Therapeutic Antibody Targeting B7-H4, For The Treatment Of Malignancies.

Abstract Human B7 homolog 4 (B7-H4) is a transmembrane protein in the B7 family of molecules that is expressed on tumor cells in the tumor microenvironment (TME). High protein expression on tumors and low expression on healthy tissue makes B7-H4 an attractive molecule for direct targeting with low off-target toxicity. NC762 is a humanized immunoglobulin gamma 1, kappa (IgG1κ) monoclonal antibody specific for human B7-H4 that is being developed for the treatment of cancer and demonstrates an excellent safety profile in IND-enabling studies. The IgG1κ region of NC762 contains three-point mutations (S239D/A330L/I332E a.k.a. DLE) which enhances binding to CD16a (FcγRIIIa) in order to increase antibody-dependent cellular cytotoxicity (ADCC) activity. NC762 binds to human B7-H4 on SKBR3 cells, a breast cancer cell line that endogenously expresses B7-H4 and induces in vitro ADCC activity. Despite the high homology, NC762 does not cross-react with rodent B7-H4, therefore, in vivo testing was performed in a humanized xenograft murine model in NSG mice, where NC762 restricted tumor growth in a dose-dependent manner. Depleting human natural killer (NK) cells prior to tumor inoculation reduced anti-B7-H4 parent antibody activity, supporting a role for NK-cell mediated ADCC in tumor growth retardation. However, in the absence of human PBMCs, NC762 also achieved significant anti-tumor activity. Furthermore, a mutant of NC762 with a low FcγR binding IgG1 domain showed similar activity as the DLE IgG1, demonstrating an ADCC-independent mechanism of tumor growth restriction mediated by B7-H4 mAb treatment. Together, these results indicate that even with the ADCC-enhanced IgG1κ region, NC762 is able to mediate ADCC-independent anti-tumor activity for the eradication of B7-H4 expressing tumors; and is expected to provide benefit in multiple oncology indications. Citation Format: Kristina Archer, Justine Ceradoy, Tiffany Coupet, Jason Bosiacki, Chang Song, Ido Weiss, Sue Niu, Tete Obot, Jinglin Xu, Tom O'Neill, Alison Ferrell, Hasan Abukharma, Zac Cusumano, Dallas Flies, Sol Langermann, Linda N. Liu. Development and functional characterization of NC762, a novel therapeutic antibody targeting B7-H4, for the treatment of malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3193.