Abstract 3816: Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models

CD40 on antigen presenting cells plays a critical role in the induction of effective innate and adaptive immune responses. In contrast, CD40 signaling on certain malignant cells, particularly B cell lymphomas, inhibits proliferation or triggers apoptotic cell death. Thus, two independent mechanisms provide opportunities for the use of agonist anti-CD40 monoclonal antibodies in cancer therapy: enhancement of anti-tumor immunity, and direct inhibition of tumor growth. CDX-1140 is a human IgG2 antibody selected from a panel of fully human mAbs specific for CD40 generated by hybridoma technology from human Ig transgenic mice. We previously demonstrated the potent immune enhancing effects of CDX-1140 using in vitro models and in non-human primates. CDX-1140 was shown to activate dendritic cells and B cells in an Fc receptor independent manner. CDX-1140 does not bind to the CD40L binding site, and synergizes with CD40L in stimulation of the CD40 receptor and subsequent functional activities. Here we further characterized the anti-tumor activity of CDX-1140 on CD40 positive tumors using xenograft models in immunodeficient mice. Using the Ramos and Raji human lymphoblastoma cell lines, CDX-1140 was shown to attenuate tumor growth and prolong survival. Addition of CDX-1140 and human PBMC was highly effective at promoting complete rejection of both Ramos and Raji tumors. Importantly, the epithelial EJ138 bladder carcinoma cell line was also highly sensitive to CDX-1140 treatment. For example, in a study where mice received EJ138 cells subcutaneously, all animals that were treated with 300 µg of CDX-1140 on days 1, 8, and 15, showed suppression of tumor growth through day 60, in comparison to saline-treated animals which developed significant tumors in 7 of 8 animals. These data support the potential of CDX-1140 for direct anti-tumor effects on CD40-positive tumors (including epithelial tumors) that may supplement its activity as an immune activating agent. CDX-1140 is currently in a phase 1 dose-escalation study in patients with advanced solid tumors. Citation Format: Lawrence J. Thomas, Li-Zhen He, James Testa, Anna Wasiuk, Jeffrey Weidlick, Crystal Sisson, Laura A. Vitale, Thomas O9Neill, Eric Forsberg, Catherine D. Pilsmaker, Lauren E. Gergel, Elizabeth Q. Do, James Boyer, April R. Baronas, Mallary Rocheleau, Michelle E. Grealish, Kathleen M. Borrelli, Henry C. Marsh, Tibor Keler. Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3816.