Abstract 6367: BSI-507, a first-in-class bispecific antibody targeting PD1 and PVRIG for cancer immunotherapy

Abstract Introduction: Despite the success of anti-PD1/PDL1 therapies, only a small fraction of patients benefit from these checkpoint inhibitors (CPIs). Novel approaches to improve outcomes for patients who are resistant to current CPIs are needed. PVRIG is expressed on CD4+ and CD8+ T cells, NKT and NK cells. PVRIG binds with high affinity with its ligand PVRL2, which is expressed on tumor cells and some myeloid cells. The PVRIG-PVRL2 axis exerts an inhibitory effect on the cytotoxic activity of lymphocytes. Bispecific antibodies that exhibit dual blockade of PD1 and PVRIG provide a promising strategy to enhance anti-tumor immune response. Methods: An anti-PD1 mAb was identified from PD1 KO mice immunized with PD1-ECD-Fc and screened by our proprietary H3 (High-throughput, High-content and High-efficiency) platform. An anti-PVRIG mAb was identified from rats immunized with recombinant PVRIG-ECD-Fc and screened by the H3 platform. Both anti-PD1 and anti-PVRIG antibodies were humanized, and the anti-PD1 scFv was fused to the N-terminus of the heavy chain of the anti-PD1 antibody via a flexible linker. The binding activities and affinities were evaluated by ELISA, FACS and SPR, and the ligand blocking activities were measured by ELISA and FACS. Cell-based reporter assays were used to evaluate the functions of the anti-PD1 and anti-PVRIG mAbs alone and the bispecific antibody. In addition, the activity of the bispecific antibody to reverse PD1 and PVRIG mediated suppression of CMV pp65495-503 antigen specific CD8+ T-cell cytotoxicity was evaluated. Results: BSI-507, an anti-PD1xanti-PVRIG bispecific antibody demonstrated comparable activity to the parental anti-PD1 antibody regarding PD1 binding and PD1/PDL1 blocking. It also exhibited comparable activity to the parental anti-PVRIG antibody in PVRIG binding and PVRIG/PVRL2 blocking. Based on cell-based reporter assays, BSI-507 was able to reverse either PD1 or PVRIG mediated T-cell suppression and exhibited comparable potency to the parental antibodies. BSI-507 was also able to show enhanced reversal of both PD1 and PVRIG mediated T-cell suppression, much better than anti-PD1 or anti-PVRIG alone. In addition, BSI-507 showed the ability to reverse PD1 and PVRIG mediated suppression of CMV pp65495-503 antigen specific CD8+ T-cell cytotoxicity, stronger than either the anti-PD1 or anti-PVRIG monoclonal antibody. Summary: BSI-507 is a first-in-class anti-PD1xanti-PVRIG bispecific antibody for dual blockade of PD-1 and PVRIG pathways to enhance reversal of T cell inhibition. BSI-507 demonstrates favorable biophysical and functional characteristics, supporting the initiation of development activities including manufacturing and IND-enabling studies. Citation Format: Zeyu Peng, Xiaodong F. Liu, Hongyan Li, Wenwen Dai, Jinyu Liu, Xiaoyao Hao, Shukai Xia, Qun Lv, Hugh M. Davis, Mingjiu Chen, Mark Z. Ma. BSI-507, a first-in-class bispecific antibody targeting PD1 and PVRIG for cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6367.