A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade

• Published in: Nature communications 2021-07, Vol.12 (1), p.4445-19, Article 4445
• Main Authors: Geuijen, Cecile, Tacken, Paul, Wang, Liang-Chuan, Klooster, Rinse, van Loo, Pieter Fokko, Zhou, Jing, Mondal, Arpita, Liu, Yao-bin, Kramer, Arjen, Condamine, Thomas, Volgina, Alla, Hendriks, Linda J. A., van der Maaden, Hans, Rovers, Eric, Engels, Steef, Fransen, Floris, den Blanken-Smit, Renate, Zondag-van der Zande, Vanessa, Basmeleh, Abdul, Bartelink, Willem, Kulkarni, Ashwini, Marissen, Wilfred, Huang, Cheng-Yen, Hall, Leslie, Harvey, Shane, Kim, Soyeon, Martinez, Marina, O’Brien, Shaun, Moon, Edmund, Albelda, Steven, Kanellopoulou, Chrysi, Stewart, Shaun, Nastri, Horacio, Bakker, Alexander B. H., Scherle, Peggy, Logtenberg, Ton, Hollis, Gregory, de Kruif, John, Huber, Reid, Mayes, Patrick A., Throsby, Mark
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/21; 13/31; 14/19; 4-1BB Ligand - agonists; 4-1BB Ligand - immunology; 49/23; 631/154/51/1568; 631/250/251; 631/67/1059/2325; 64/60; 692/699/67/1059/2325; Agonists; Animal models; Animals; Antibodies; Antibodies, Bispecific - immunology; Antibodies, Bispecific - pharmacology; Anticancer properties; Antitumor activity; Antitumor agents; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Biocompatibility; Bispecific antibodies; CD137 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell differentiation; Comparators; Epitopes; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - immunology; Immune Checkpoint Inhibitors - pharmacology; Immune Tolerance - drug effects; Immunologic Memory - drug effects; Immunological memory; Immunotherapy; Inhibitors; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Memory cells; multidisciplinary; PD-1 protein; PD-L1 protein; Primates; Priming; Science; Science (multidisciplinary); Toxicity; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24767-5

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. The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.