Evaluating Anti-PD-1/CD40 In Vivo Efficacy and Safety on Humanized Double Knock-in Mice
Over the past years, monoclonal antibodies have been successfully utilized in clinical trials to block or active key mediators of immune checkpoint pathways. However, along the IO drug development process, in vivo efficacy models have always been a rate-limiting step, especially for the 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 can “wake” DC to prime effective cytotoxic T-cell responses. Thus, anti-CD40 antibody provides an ideal therapy combination with other IO antibodies.
To evaluate the in vivo efficacy and safety (immune-related adverse events) of CD40 and PD-1 combination, we developed a double humanized B-hPD-1/hCD40 mouse model. 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 shows higher inhibitory effects than single antibody treatments. The blood chemistry assays showed that the CD40 antibody had no toxicity compared with control group.