Humanized Knock-In Mouse Models For Evaluating In Vivo Efficacy Of Immune-Oncology Drugs Targeting Inhibitory Immune Checkpoint Molecules

Recently, increasingly attention has been paid to the development of immuno-oncology (IO) drugs, due to the promising clinical results acquired by CTLA-4, PD-1 and PD-L1 antibodies. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step. Mouse surrogate antibodies were often used in immune-competent mice with murine syngeneic tumor models to evaluate in vivo efficacy of the IO drugs. However, the efficacy of a surrogate antibody cannot fully represent the human drug in the clinical scenario. In most cases, a human monoclonal antibody does not have mouse cross-reactivity. Therefore, we generated humanized knock-in mouse to evaluate the in vivo efficacy of human IO antibodies. For example, human PD-1 knock-in (B-hPD-1) mice were generated with a chimeric PD-1 receptor, which is recognizable by human PD-1 antibodies, and can be used to test human PD-1 antibody in vivo efficacy. Mouse cancer cell lines including colon cancer MC38, melanoma B16F10 and lung cancer LLC1 were genetically modified with over-expression of hPD-L1 and knock-out of mPD-L1, and used to evaluate the in vivo efficacy of human PD-L1 antibodies. Additionally, more knock-in mice targeting inhibitory immune checkpoint molecules were developed, such as B-hPD-L1, B-hCTLA-4, B-hLAG3, B-hTIM3, B-hTIGIT, B-hBTLA, B-hSIRPa et al,. Humanized knock-in mice, pairing with genetically modified mouse cancer cells, represent a promising in vivo efficacy model for the development of IO drugs, and contribute to the clinical translation of animal studies. Citation Format: Baozhu Zhang, Chaoshe Guo, Yuelei Shen, Yanan Guo. Humanized knock-in mouse models for evaluating in vivo efficacy of immune-oncology drugs targeting inhibitory immune checkpoint molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1149.