A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
Cecile Geuijen, Paul J. Tacken, Liang-Chuan Wang, Rinse Klooster, Pieter Fokko van Loo, Jing Zhou, Arpita Mondal, Yao-Bin Liu, Arjen Kramer, Thomas Condamine, Alla Volgina, Linda Hendriks, Hans van der Maaden, Eric Rovers, Steef Engels, Floris Fransen, Renate den Blanken-Smit, Vanessa Zondag-van der Zande, Abdul Basmeleh, Willem Bartelink, Ashwini Kulkarni, Wilfred E. Marissen, Cheng‐Yen Huang, Leslie Hall, Shane Harvey, Soyeon Kim, Marina C. Martinez, Shaun O’Brien, Edmund K. Moon, Steven Μ. Albelda, Chrysi Kanellopoulou, Shaun Stewart, Horacio Nastri, Alexander B. H. Bakker, Peggy Scherle, Ton Logtenberg, Gregory Hollis, John de Kruif, Reid Huber, Patrick A. Mayes, Mark Throsby
Abstract
Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations. MCLA-145 potently activates T cells at sub-nanomolar concentrations, even under suppressive conditions, and enhances T cell priming, differentiation and memory recall responses. In vivo, MCLA-145 anti-tumor activity is superior to immune checkpoint inhibitor comparators and linked to recruitment and intra-tumor expansion of CD8 + T cells. No graft-versus-host-disease is observed in contrast to other antibodies inhibiting the PD-1 and PD-L1 pathway. Non-human primates treated with 100 mg/kg/week of MCLA-145 show no adverse effects. The conditional activation of CD137 signaling by MCLA-145, triggered by neighboring cells expressing >5000 copies of PD-L1, may provide both safety and potency advantages.