 A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockadeCecile Geuijen,
Paul Tacken,
Liang-Chuan Wang,
Rinse Klooster,
Pieter Fokko Loo,
Jing Zhou,
Arpita Mondal,
Yao-bin Liu,
Arjen Kramer,
Thomas Condamine,
Alla Volgina,
Linda J. A. Hendriks,
Hans Maaden,
Eric Rovers,
Steef Engels,
Floris Fransen,
Renate Blanken-Smit,
Vanessa Zondag- van der Zande,
Abdul Basmeleh,
Willem Bartelink,
Ashwini Kulkarni,
Wilfred Marissen,
Cheng-Yen Huang,
Leslie Hall,
Shane Harvey,
Soyeon Kim,
Marina Martinez,
Shaun O’Brien,
Edmund Moon,
Steven Albelda,
Chrysi Kanellopoulou,
Shaun Stewart,
Horacio Nastri,
Alexander B. H. Bakker,
Peggy Scherle,
Ton Logtenberg,
Gregory Hollis,
John Kruif,
Reid Huber,
Patrick A. Mayes () and
Mark Throsby ()
Nature Communications, 2021, vol. 12, issue 1, 1-19 Abstract: 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. Date: 2021 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24767-5 Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-021-24767-5 Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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