Abstract 3241: Novel anti-CD40 antibodies demonstrate anti-tumor activity in humanized mouse models

Abstract

Abstract CD40 (Cluster of Differentiation 40) is a member of the TNF-receptor superfamily. CD40 is a co-stimulatory protein found primarily on antigen presenting cells, including B cells, macrophages and dendritic cells. Its ligand, CD40L (CD154) is predominantly expressed on T helper cells, whose engagement activates antigen presenting cells and induces a variety of positive downstream effects. Whereas most immune checkpoint receptors are expressed on the surface of T cells, CD40 stands out as it is expressed by antigen presenting cells and controls the proper activation of these cells. In turn, CD40 activation exerts a significant impact on T cell-mediated activity against cancer cells. Several pharmaceutical companies are pursuing anti-CD40 therapies for treating hematological and solid cancers. Therefore, it is imperative to develop novel CD40 antibodies to boost cancer patients’ own immunity in light of other successful immune checkpoint modulators. We asked whether we could find suitable anti-CD40 reagents that successfully combat developed tumors in preclinical settings. We designed a powerful screening strategy based on Biocytogen’s in vivo drug screening platform. Candidate antibodies were generated by immunizing wild-type mice with recombinant hCD40 protein. Hybridomas were then screened by high-throughput flow cytometry. Instead of examining the immune modulating activity in cell culture, we tested these antibodies in B-hCD40 mice bearing MC38 tumors and monitored the tumor growth. Through this straightforward screening strategy, several clones stood out by their unparalleled benefits. These clones were further selected for humanization. Furthermore, we identified that one clone works in concert with Keytruda in the dual humanized model of h-CD40 and h-PD1. In conclusion, we uncovered CD40 antibody candidates with the most potent anti-tumor activity which are promising as tools for cancer treatment in the preclinical setting. Citation Format: Chaoshe Guo, Benny(Yi) Yang, Jian Ni, Yanan Guo, Tian Gan. Novel anti-CD40 antibodies demonstrate anti-tumor activity in humanized mouse models [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 3241.