A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
In: Nature Communications Nature Communications, Jg. 12 (2021), Heft 1, S. 1-19
Online
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Zugriff:
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.
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A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade
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Autor/in / Beteiligte Person: | Albelda, Steven M. ; Engels, Steef ; Kim, Soyeon ; Volgina, Alla ; Fransen, Floris ; Linda Johanna Aleida Hendriks ; Geuijen, Cecile ; Harvey, Shane ; Nastri, Horacio ; Huber, Reid ; Hall, Leslie ; Hollis, Gregory ; John de Kruif ; Zhou, Jing ; Basmeleh, Abdul ; Pieter Fokko Van Loo ; Throsby, Mark ; Moon, Edmund K. ; Kramer, Arjen ; Bartelink, Willem ; Rovers, Eric ; Tacken, Paul ; Hans van der Maaden ; Vanessa Zondag-van der Zande ; Cheng Yen Huang ; Klooster, Rinse ; Liang Chuan Wang ; Kulkarni, Ashwini ; Kanellopoulou, Chrysi ; Martinez, Marina ; Marissen, Wilfred E. ; O'Brien, Shaun ; Alexander Berthold Hendrik Bakker ; Logtenberg, Ton ; Renate den Blanken-Smit ; Stewart, Shaun ; Scherle, Peggy ; Mondal, Arpita ; Mayes, Patrick ; Yao bin Liu ; Condamine, Thomas |
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Zeitschrift: | Nature Communications Nature Communications, Jg. 12 (2021), Heft 1, S. 1-19 |
Veröffentlichung: | Nature Publishing Group UK, 2021 |
Medientyp: | unknown |
ISSN: | 2041-1723 (print) |
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