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Ref Type Journal Article
PMID (32161196)
Authors Eskiocak U, Guzman W, Wolf B, Cummings C, Milling L, Wu HJ, Ophir M, Lambden C, Bakhru P, Gilmore DC, Ottinger S, Liu L, McConaughy WK, He SQ, Wang C, Leung CL, Lajoie J, Carson WF, Zizlsperger N, Schmidt MM, Anderson AC, Bobrowicz P, Schuetz TJ, Tighe R
Title Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity.
Journal Vol Issue Date Pages Journal Short Title
JCI insight 5 5 2020 Mar 12 JCI Insight
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CTX-471 CTX-471 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
CTX-471 CTX471|CTX 471|anti-4-1BB agonistic monoclonal antibody TNFRSF9 Antibody 30 CTX-471 is an agonistic antibody that binds to CD137 (4-1BB), which potentially activates immune cells resulting in reduced tumor growth (PMID: 32161196).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References