Two agonistic antibody therapies targeting CD137 (4-1BB) resulted in hepatotoxicity and poor efficacy in the clinic. To improve these profiles, Eskiocak et al. developed CTX-471, an IgG4-Fc anti-CD137 antibody which regressed exceptionally large tumors in mouse models without inducing spleen or liver toxicities. CTX-471 binding was not competitive with, and synergized with CD137 ligand binding. Efficacy depended on both T and NK cells, as well as Fc receptor engagement with IgG4. Treatment increased colon carcinoma T cell infiltration, reduced intratumoral Tregs and exhaustion marker expression, and enriched for memory signatures.
Contributed by Alex Najibi
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-gamma production by human T cells in an Fcgamma receptor-dependent (FcgammaR-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.
Author Info: (1) Compass Therapeutics, Cambridge, Massachusetts, USA. (2) Compass Therapeutics, Cambridge, Massachusetts, USA. (3) Compass Therapeutics, Cambridge, Massachusetts, USA. (4) Compa
Author Info: (1) Compass Therapeutics, Cambridge, Massachusetts, USA. (2) Compass Therapeutics, Cambridge, Massachusetts, USA. (3) Compass Therapeutics, Cambridge, Massachusetts, USA. (4) Compass Therapeutics, Cambridge, Massachusetts, USA. (5) Compass Therapeutics, Cambridge, Massachusetts, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA. (6) Compass Therapeutics, Cambridge, Massachusetts, USA. (7) Compass Therapeutics, Cambridge, Massachusetts, USA. (8) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA. (9) Compass Therapeutics, Cambridge, Massachusetts, USA. (10) Compass Therapeutics, Cambridge, Massachusetts, USA. (11) Compass Therapeutics, Cambridge, Massachusetts, USA. (12) Compass Therapeutics, Cambridge, Massachusetts, USA. (13) Compass Therapeutics, Cambridge, Massachusetts, USA. (14) Compass Therapeutics, Cambridge, Massachusetts, USA. (15) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA. (16) Compass Therapeutics, Cambridge, Massachusetts, USA. (17) Compass Therapeutics, Cambridge, Massachusetts, USA. (18) Compass Therapeutics, Cambridge, Massachusetts, USA. (19) Compass Therapeutics, Cambridge, Massachusetts, USA. (20) Compass Therapeutics, Cambridge, Massachusetts, USA. (21) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA. (22) Compass Therapeutics, Cambridge, Massachusetts, USA. (23) Compass Therapeutics, Cambridge, Massachusetts, USA. (24) Compass Therapeutics, Cambridge, Massachusetts, USA.
