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

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 7

High doses of CTX-471 and CTX-471-AF do not induce hepatic inflammation.

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High doses of CTX-471 and CTX-471-AF do not induce hepatic inflammation....
(A–I) Nontumor-bearing mice (n = 4 in each treatment group) were administered with 10–80 mg/kg CTX-471, CTX-471-AF, or 3H3 i.v. on days 0, 7, 14, and 21. Plasma, spleens, and livers were collected on day 28. Alanine aminotransferase (ALT) activity (A) and TNF-α (B) concentrations were determined from plasma. CD8+ T cell (C) levels in the livers were determined by flow cytometry. Formalin-fixed paraffin-embedded tissues were stained for H&E (D) or with antibodies against CD8 (E and F) and F4/80 (G–I). Mean cell densities of CD8+ cells (F) and F4/80+ cells (H), and number of F4/80 clusters (I; defined as > 10 cells), are shown. Scale bars: 200 μm. Arrowheads indicate lymphocyte clusters. (J) Mouse BM-derived macrophages were stimulated with CpG ODN (10 μg/mL), along with the indicated soluble antibodies (50 nM), for 48 hours, and levels of TNF-α and IL-27 were measured in supernatants. (K) Primary human monocyte–derived macrophages were stimulated with CpG ODN (10 μg/mL), along with the indicated soluble antibodies (50 nM) for 48 hours, and levels of TNF-α and IL-27 are measured in supernatants. One-way ANOVA with Bonferroni’s post hoc test was performed to determine the statistical significance of treatment versus control (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001).