Abstract B28: Improved therapeutic activity of agonistic, human anti-CD40 monoclonal Abs by selective FcγR-engagement

Abstract

Abstract The use of immunomodulatory mAbs to stimulate effective therapeutic anticancer immunity has shown clinical successes for the treatment of an increasing number of cancer types. An approach that is currently under clinical development uses agonistic anti-CD40 mAbs to induce APC activation, thereby harnessing the potency of the immune response to eradicate tumors. While engagement of the inhibitory Fcγ Receptor(FγγR)IIB is required for the in vivo agonistic activity of anti-mouse CD40 mAbs, a similar requirement for human mAbs has been disputed based on in vitro studies and in vivo studies performed either in wild-type or mouse FcγR knockout strains and thus fails to address the unique binding affinities and tissue distribution of human FcγRs. To overcome these limitations we generated and used unique mouse model fully humanized for its FcγRs and CD40, and revealed that FcγRIIB engagement is also essential for the activity of the human CD40 agonistic mAbs, while engagement of the activating FcγRIIA inhibits their activity. By engineering Fc variants of human mAbs with selective enhancement to FcγRIIB but not to FcγRIIA, significant improvement of antitumor immunity was observed in multiple tumor models. These findings highlight the necessity of optimizing the Fc domain for this class of therapeutic antibodies by using pre-clinical model that accurately reflects the unique affinities and cellular expression of human FcRs, thus providing a development approach for therapeutic human antibodies based on their requirement for selective FcγR interactions. Here we describe the selection of optimized next-generation Fc-engineered agonistic CD40 mAbs. Citation Format: Rony Dahan, Bryan C. Barnhart, Alan J. Korman, Jeffrey V. Ravetch. Improved therapeutic activity of agonistic, human anti-CD40 monoclonal Abs by selective FcγR-engagement. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B28.