Development and characterization of a novel human CD137 agonistic antibody with anti‐tumor activity and a good safety profile in non‐human primates. Issue 12 (9th October 2022)

• Record Type: Journal Article
• Authors: Gao, Yingying; Yang, Teddy; Liu, Hu; Song, Ningning; Dai, Chaohui; Ding, Yu
• Is Part Of: FEBS open bio. Volume 12:Issue 12(2022)
• Page Start: 2166
• Page End: 2178
• Publication Date: 2022-10-09
• Subjects: 4‐1BB -- agonistic antibody -- cancer immunotherapies -- CD137 -- costimulatory receptors -- PE0116; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.13494
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : CD137 (4‐1BB, TNFRSF9), an inducible T‐cell costimulatory receptor, is expressed on activated T cells, activated NK cells, Treg cells, and several innate immune cells, including DCs, monocytes, neutrophils, mast cells, and eosinophils. In animal models and clinical trials, anti‐CD137 agonistic monoclonal antibodies have shown anti‐tumor potential, but balancing the efficacy and toxicity of anti‐CD137 agonistic monoclonal antibodies is a considerable hindrance for clinical applications. Here, we describe a novel fully human CD137 agonistic antibody (PE0116) generated from immunized harbor H2L2 human transgenic mice. PE0116 is a ligand blocker, which is also the case for Utomilumab (one of the leading CD137 agonistic drugs); PE0116 partially overlaps with Urelumab's recognized epitope. In vitro, PE0116 activates NF‐κB signaling, significantly promotes T‐cell proliferation, and increases cytokine secretion in the presence of cross‐linking. Importantly, PE0116 possesses robust anti‐tumor activity in the MC38 tumor model. In vivo, PE0116 exhibits a good safety profile and has typical pharmacokinetic characteristics of an IgG antibody in preclinical studies of non‐human primates. In summary, PE0116 is a promising anti‐CD137 antibody with a good safety profile in preclinical studies. Abstract : We developed a CD137 agonistic antibody (PE0116) with good anti‐tumor activity and a good safety profile for clinical development. In vitro, PE0116 promotes proliferation and activation of T cells with cross‐linking. In vivo, PE0116 shows robust anti‐tumor potency in mouse tumor models and a manageable safety profile in cynomolgus macaques, with no appearance of elevated liver enzymes, thrombocytopenia, or neutropenia.