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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 6

CTX-471 efficacy requires T and NK cells, as well as FcγR engagement.

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CTX-471 efficacy requires T and NK cells, as well as FcγR engagement.
(A...
(A) Effect of CTX-471 on tumor growth in the absence of T cells. Mice (n = 10 per group) were depleted of T cells by administering 500 μg/mouse of CD4 (GK1.5) or CD8 (YTS 169.4) antibodies on days –1, 0, 5, 10, 15, and 20 after CT-26 tumor cell implantation. Mice received 150 μg/mouse CTX-471 on days 6, 9, 12, 19, and 26. (B) Effect of CTX-471 on tumor growth in the absence of NK cells. Mice (n = 8 per group) were depleted of NK cells by administering 50 μL/mouse of asialo-GM1 antibody (anti-ASGM1) on days –1, 0, 5, 10, 15, and 20 after CT-26 tumor cell implantation. Mice received 150 μg/mouse CTX-471 on days 7, 10, 13, 20, and 27. (C) Effect of CTX-471 on overall survival in the absence of FcγR engagement. Mice with established CT-26 tumors were treated with 150 μg/mouse of CTX-471-AF or CTX-471 with human IgG4, aglycosylated human IgG4, or rat IgG2a isotypes on days 0, 3, 6, and 9. (D) Flow cytometric analysis of CT-26 tumor infiltrating Tregs on day 9 following administration of CTX-471 with hIgG4 or rIgG2a isotype on days 0, 3, and 6. Statistical significance was determined using Log-rank test (C) or 1-way ANOVA (D) followed by Bonferroni’s multiple comparison test compared with control treatment groups (*P<0.05, **P<0.01, ****P<0.0001). All data presented as mean ± SEM.

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