2. Academic Validation
  3. Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity

Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity

  • JCI Insight. 2020 Mar 12;5(5):e133647. doi: 10.1172/jci.insight.133647.
Ugur Eskiocak 1,  Wilson Guzman 1,  Benjamin Wolf 1,  Christine Cummings 1,  Lauren Milling 1 2,  Hsin-Jung Wu 1,  Michael Ophir 1,  Conner Lambden 3,  Pearl Bakhru 1,  Dana C Gilmore 1,  Samantha Ottinger 1,  Lucy Liu 1,  William K McConaughy 1,  Sunny Q He 1,  Chao Wang 3,  Cheuk Lun Leung 1,  Jason Lajoie 1,  William F Carson 4th 1,  Nora Zizlsperger 1,  Michael M Schmidt 1,  Ana C Anderson 3,  Piotr Bobrowicz 1,  Thomas J Schuetz 1,  Robert Tighe 1
Affiliations

Affiliations

  • 1 Compass Therapeutics, Cambridge, Massachusetts, USA.
  • 2 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
  • 3 Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.
PMID: 32161196 DOI: 10.1172/jci.insight.133647
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.

Keywords

Immunology; Immunotherapy; Oncology.

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