Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity
Uğur Eskiocak, Wilson Guzman, Benjamin Wolf, Christine L. Cummings, Lauren E. Milling, Hsin‐Jung Joyce Wu, Michael Ophir, Conner Lambden, Pearl Bakhru, Dana C. Gilmore, Samantha Ottinger, Lucy Liu, William McConaughy, Sunny Q. He, Chao Wang, Cheuk Lun Leung, Jason Lajoie, William F. Carson, Nora Zizlsperger, Michael M. Schmidt, Ana C. Anderson, Piotr Bobrowicz, Thomas Schuetz, Robert M. Tighe
Abstract
CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here, we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an Fcγ receptor-dependent (FcγR-dependent) manner, displaying an intermediate level of activity between 2 clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared with validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that displays an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.