Abstract 5199: B7-H3 & PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies

Abstract

Abstract Immune checkpoint molecule B7-H3, also known as CD276, is a member of the B7-CD28 family of immunomodulatory proteins. It is a type I membrane protein with sequence similarities to the extracellular domain of programmed death-ligand 1 (PD-L1). B7-H3 is highly expressed in most human cancers, but has limited distribution in normal tissues, remaining elusive of its receptor. Due to its promising safety as a dominant tumor target, various strategies have been developed to modulate the effect of B7-H3 via monoclonal antibodies, bispecific antibodies, ADC, or CAR-T. To study the effect of these therapies in an immunocompetent mouse model, we established a double humanized B7-H3 and PD-L1 mouse model on BALB/c background (BALB/c-hB7-H3/hPD-L1). In this model, the extracellular domain of murine fragments was replaced by the human counterparts while the trans-membrane and cytoplasmic domain were kept intact. When engrafted with CT26 colon cancer cells, which stably overexpress human B7-H3 and PD-L1 while endogenous murine counterparts were knocked out, the tumor growth was inhibited certain degree by anti-B7-H3 antibody (8H9 Biosimilar, 20mpk, TGI=18.56%) treatment while inhibited significantly after the monotherapy of anti-PD-L1 (Tecentriq, 3 mpk, TGI=55.89%, p<0.001). The same dosage combination of anti-B7-H3 and anti-PD-L1 had a significant inhibition on tumor growth (TGI=76.85%, p<0.001), and had a synergistic effect (CDI<0.7) compared with the monotherapy. Analysis of tumor-infiltrating lymphocytes (TILs) at the end of the efficacy study showed that the proportion of CD45+ immune cells was significantly increased in all of the treated groups. The NK cells were significantly increased and the Treg cells were significantly decreased especially in the combined treatment group. Based on the above, the B7-H3 and PD-L1 double humanized mouse model is suitable for the pre-clinical evaluation of mono or combined immune checkpoint blockade with anti-human B7-H3 and PD-L1 therapy. Citation Format: Shiying Guo, Lingyu Song, Xin Qin, Jianming Xu, Hongyan Sun, Cunxiang Ju, Hongyu Wang, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. B7-H3 & PD-L1 double-humanized BALB/c mouse: a novel animal model for preclinical studies of human B7-H3 antibodies or bispecific antibodies. [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 5199.