Abstract 2667: In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1

Abstract

Abstract Monoclonal-antibody-based therapies targeting the immune checkpoint receptors have become the new standard of care in many cancers. Antibodies that specifically target programmed death receptor-1 (PD-1) or its cognate ligand, programmed death receptor ligand-1 (PD-L1), alone or in combination, have yielded clinical benefits and durable responses in patient subsets with various cancers (including metastatic melanoma, NSCLC, RCC, urothelial cancer, cHL and others). Here we report on the biophysical characteristics and non-clinical antagonistic activities of PF-06801591. PF-06801591 is a humanized anti-PD-1 antibody of human IgG4 isotype, that binds selectively and with similar potency to human and cynomolgus monkey PD-1 receptor (EC50 ~50 pM) and blocks its interaction with its cognate ligands PD-L1 and PD-L2 (IC50 < 1 nM) with no detectable Fc effector function. The interaction of PF-06801591 to PD-1 rescues T cell suppression and exhaustion that translates into NFAT activation, IL-2 and IFN-gamma secretion and T cell proliferation both in vitro cultures and in vivo using an acute xeno GvHD model with human PBMC transfer. Binding of PF-068001591 to human and cynomolgus PD-1 is characterized by the formation of a very stable complex (T1/2 = 2 h) as measured by SPR at 37 C, resulting in high affinity (KD ~20 pM) as measured in solution by KinExA at 23 C. In addition, we explored therapeutic potential of anti-PD-1 in combination with other immunotherapy agents using surrogate antibodies in non-clinical tumor models. The data presented here support future development of PF-06801591 as a single agent or in combination with other immunotherapies. Citation Format: Sawsan Youssef, Yasmina Abdiche, HoangKim Nguyen, Joyce Chou, Sherman Michael Chin, Cris Kamperschroer, Patricia A. Schneider, Eugenia Kraynov, Heike I. Krupka, Arvind Rajpal, John Lin. In vitro properties and pre-clinical activity of PF-06801591, a high-affinity engineered anti-human PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2667. doi:10.1158/1538-7445.AM2017-2667