Development of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function. The binding of sasanlimab to human and cynomolgus PD-1 is associated with the formation of a stable complex, which is likely to be the main driver of this high-affinity interaction. In vitro, sasanlimab significantly augmented T-cell proliferation and cytokine production in mixed lymphocyte reaction and superantigen stimulation assays. In vivo, sasanlimab accelerated the incidence of GvHD by enhancing T-cell proliferation and cytokine secretion in a xenogeneic model of acute GvHD and halted the growth of MC-38 colon adenocarcinoma tumors in human PD-1 knock-in mice. Pharmacokinetic and toxicokinetic findings from cynomolgus monkey showed that sasanlimab was active and well-tolerated. Taken together, the data presented here support the clinical development of sasanlimab for the treatment of patients with advanced cancers as a single agent or in combination with other immunotherapies.
Molecular cancer therapeutics. 2020 Aug 26 [Epub]
Amir A Al-Khami, Sawsan Youssef, Yasmina Abdiche, HoangKim Nguyen, Joyce Chou, Christopher R Kimberlin, Sherman M Chin, Cris Kamperschroer, Bart Jessen, Brent Kern, Natalija Budimir, Christopher P Dillon, Allison Xu, Jerry D Clark, Jeffrey Chou, Eugenia Kraynov, Arvind Rajpal, John C Lin, Shahram Salek-Ardakani
Cancer Immunology Discovery, Pfizer Inc., San Diego, California., Drug Safety R&D, Pfizer Inc., San Diego, California., BioMedicine Design, San Diego, California., In vivo Pharmacology, San Diego, California., Pharmaceutical Sciences, Pfizer Global R&D, St. Louis Laboratories, Pfizer Inc., St. Louis, Missouri., Cancer Immunology Discovery, Pfizer Inc., San Diego, California. .