The CD40 (also known as TNFRSF5) and its ligand CD40L (also known as CD154) belong to the TNF/TNFR family. CD40 is expressed on antigen presenting cells (APCs), including B cell, monocytes, macrophages and dendritic cells. CD40-CD40L is a pair of costimulatory molecules that, after interacting at the cell surface, promotes intracellular signaling by recruiting TNFR-associated factor (TRAF) in the cytosol, thereby activating multiple downstream signaling pathways. Therapeutic targeting of CD40 by agonistic monoclonal antibodies (mAbs) aims to activate CD40+ APCs to effectively boost tumor-specific cytotoxic T cells to eliminate tumor cells. In principle it has the advantage of greater tumor specificity over other T cell activating approaches, such as checkpoint inhibition or indiscriminate T cell activation.
We are interested in developing a novel immune checkpoint monoclonal antibody that targets CD40 and can treat cancer patients. Using Biocytogen's antibody research platform, dozens of candidate antibodies were obtained by classical hybridoma technology as well as high-throughput flow cytometry screening. Next, these murine antibodies were screened directly in humanized mouse models (B-hCD40) bearing a syngeneic cancer cell line. We discovered candidates that have potent anti-tumor activity in vivo. These candidate antibodies were further humanized, and we found an antibody called YH003 with potent antitumor activity in the MC38 tumor model. Fortunately, YH003 was able to inhibit tumor growth in combination with Pembrolizumab in the double humanized model of h-CD40 and h-PD1 bearing a syngeneic B16F10 cancer cell line. In vitro studies demonstrated that YH003 bound specifically and potently to human and monkey CD40 proteins, we used cynomolgus monkeys to further explore the safety evaluation. In conclusion, we use Biocytogen's in vivo drug screening platform to obtain more novel CD40 antibodies with anti-tumor activity in addition to YH003, accelerating the progress of preclinical antibody discovery.
Citation Format: Yi Yang, Zhihong Li, Yu Zhu, Jingshu Xie, Yunyun Chen. In vivo drug screening platform accelerates anti-hCD40 antibody drug discovery [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6307.