Abstract 1495: Alternative humanized PD-1 mouse models provide more options for PD-1 antibody efficacy study in vivo

Abstract

Abstract The Programmed Death-1 (PD-1) binding to its ligands PD-L1 and PD-L2 plays a critical role in suppression of T cell function and tumor immune evasion. Blocking antibodies against PD-1 have been shown to induce durable antitumor responses in multiple cancers in many clinical trials. So a well-characterized mouse model is essential for preclinical studies of antibodies that target human PD-1. Here we generated several humanized PD-1 knock-in mouse models, one expresses a hybrid PD1 protein by replacing the amino acids that involve in binding to PD-L1 (mostly IgV domain) with the human counterpart in both C57BL/6J and Balb/C genetic background, another one have both the IgV domain and signal peptide replaced by human counterpart. These mouse models were confirmed by PCR and southern blotting. And homozygous mouse models from these different strategies were also successfully generated and both of them could survive and the birth rate were very similar to heterozygous and wild type littermates. Staining for human and mouse PD-1 in stimulated CD8+ and CD4+ T cells indicate the up regulated expression of human PD-1 and absence of mouse PD-1 in these mouse model. Homozygous human PD-1 knock-in mice displayed normal development, and no obvious signs of autoimmunity for at least six months, whereas PD-1 knockout mice developed tissue-specific autoimmunity. With these human PD-1 knock-in mice engrafted with MC38 and treated with anti-human PD-1 antibodies, we confirmed the binding of anti-human antibody to chimeric PD-1 protein, and found anti-human PD-1 antibodies could significantly inhibit tumor growth in these models. Head to head comparison of these mice with current commercial available models for in vivo efficacy studies are undergoing and will reveal how the signal peptide effect the protein refolding or signaling transduction pathway for these ‘human-mouse’ chimeric proteins. In summary, these human PD-1 knock-in mouse models are functional and can be used to evaluate anti-human PD1 antibodies in vivo, we provide more options for antibodies which is targeting PD-1. Citation Format: Qing Lin, Huimin Ma, Xiaoyu Zhang, Hengbin Li, Wenjing Yang, Zhewei Yang, Xingchen Shen, Qunsheng Ji. Alternative humanized PD-1 mouse models provide more options for PD-1 antibody efficacy study in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1495.