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Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity
Ugur Eskiocak, … , Thomas J. Schuetz, Robert Tighe
Ugur Eskiocak, … , Thomas J. Schuetz, Robert Tighe
Published March 12, 2020
Citation Information: JCI Insight. 2020;5(5):e133647. https://doi.org/10.1172/jci.insight.133647.
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Research Article Immunology Oncology

Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity

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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.

Authors

Ugur Eskiocak, Wilson Guzman, Benjamin Wolf, Christine Cummings, Lauren Milling, Hsin-Jung Wu, Michael Ophir, Conner Lambden, Pearl Bakhru, Dana C. Gilmore, Samantha Ottinger, Lucy Liu, William K. McConaughy, Sunny Q. He, Chao Wang, Cheuk Lun Leung, Jason Lajoie, William F. Carson IV, Nora Zizlsperger, Michael M. Schmidt, Ana C. Anderson, Piotr Bobrowicz, Thomas J. Schuetz, Robert Tighe

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Figure 3

CTX-471–induced activity is further enhanced by CD137 ligand.

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CTX-471–induced activity is further enhanced by CD137 ligand.
(A) HEK-Sp...
(A) HEK-SplitCD137 cells were incubated with cross-linked anti-CD137 antibodies for 4 hours. The cells were then lysed and the level of CD137 cross-linking was determined by measuring luminescence of firefly luciferase. (B–D) HEK-293T cells expressing CD137 and a minimal NF-κB reporter were cocultured in the presence of plate-bound isotype or CD137L-Fc, along with cross-linked CTX-471 (B), urelumab (C), or utomilumab (D) for 4 hours. The cells were then lysed, and the level of NF-κB signaling was determined by measuring the luminescence of firefly luciferase. All data are the average of n = 3 independent experiments, presented as mean ± SEM. (E) IFN-γ secretion after a 3-day coculture of anti-CD3 activated primary T cells with CHO-CD32b cells and CTX-471 with or without CD137L-Fc.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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