Abstract 3219: In vivo efficacy and safety evaluation of anti-human PD-1 and CD40 mAbs using double humanized PD-1/CD40 mouse model

Abstract

Abstract In recent years, monoclonal antibodies have been successfully used in clinical trials to block or activate key mediators of immune checkpoint pathways, including CTLA4, PD-1, PD-L1, CD40 and others. Combination therapy can promote antigen release and T cell priming, T cell activation and homing, which helps to overcome tumor immune-evasive mechanisms and maximize efficacy, ultimately benefitting most patients. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step, especially to test combination therapy using two IO antibodies. The transmembrane protein receptor CD40 is a member of the tumor necrosis factor (TNF) receptor super family and is involved in co-stimulation of immune cells. CD40 is expressed by antigen-presenting cells (APCs) including dendritic cells (DCs), B-cells, macrophages, and monocytes. It has the ability to "wake" DCs to prime effective cytotoxic T-cell responses. Thus, effective anti-CD40 antibodies provide an ideal therapy alternative in combination with other IO antibodies. To evaluate the in vivo efficacy and safety (immune-related adverse events) of CD40 and PD-1 combination antibodies, we developed a double humanized B-hPD-1/hCD40 mouse model. In this model, mouse PD-1 gene exon 2, and CD40 gene exons 2-7 were replaced with their human counterparts. Murine colon cancer MC38 cells were subcutaneously implanted into homozygous B-hPD-1/hCD40 mice. We compared the effect among single hPD-1 antibody Keytruda, single hCD40 antibody Selicrelumab and combination of the two. Combination treatment of Selicrelumab and Keytruda show higher inhibitory effects than single antibody treatments. The blood chemistry assays showed that the CD40 antibody had no toxicity effects compared with the control group. Based on these findings, we conclude that the B-hPD-1/hCD40 double-humanized mouse model is a powerful tool for in vivo efficacy and safety evaluation of hPD-1 and hCD40 antibodies for combination therapy. Citation Format: Yanan Guo. In vivo efficacy and safety evaluation of anti-human PD-1 and CD40 mAbs using double humanized PD-1/CD40 mouse model [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 3219.