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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 5

CTX-471 profoundly reprograms the tumor immune environment.

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CTX-471 profoundly reprograms the tumor immune environment.
(A–H) Mice w...
(A–H) Mice with established CT-26 tumors (n = 4 per group) were treated with CTX-471-AF on days 0, 3, 6, and 9. Tissues were harvested on day 11, and dissociated tumors were analyzed by flow cytometry. CD45+ tumor infiltrating leukocytes (TILs; A); fraction of CD8+ T cells (B), CD4+ T cells (C), and Tregs (D) within TILs; TIGIT+PD-1+ double-positive cells within CD8+ T cells (E), and CD4+ T cells (F); tumor associated macrophages (TAM; G) and M1 polarized TAMs (H) are shown. Statistical significance was determined using 1-way ANOVA followed by Bonferroni’s multiple comparison compared with control treatment groups (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). All data are presented as mean ± SEM. (I) t-SNE plot showing unsupervised clustering of the scRNA profiles of CD8+ TILs from CT-26 tumor–bearing mice treated with isotype, CTX-471-AF, or 3H3. t-SNE plot highlighting cells from isotype- (red), CTX-471-AF– (orange), and 3H3-treated (gray) mice. (J) Heatmap of differentially expressed genes between clusters (0, 1, and 2) that show differential enrichment in cells from isotype-, CTX-471-AF–, and 3H3-treated mice. (K) Violin plots showing expression of a memory-precursor CD8+ T cell signature (left), effector CD8+ T cell signature (middle), and a dysfunction/exhaustion signature (right) in the scRNA profiles of CD8+ TILs from isotype- (blue), CTX-471-AF– (orange), and 3H3-treated (green) mice. ***P < 0.001 by Benjamini-Hochberg corrected Tukey’s multiple comparisons test.

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