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Development and characterization of a novel human CD137 agonistic antibody with anti-tumor activity and a good safety profile in non-human primates.

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.

SUBMITTER: Gao Y

PROVIDER: S-EPMC9714380 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Development and characterization of a novel human CD137 agonistic antibody with anti-tumor activity and a good safety profile in non-human primates.

Gao Yingying Y Yang Teddy T Liu Hu H Song Ningning N Dai Chaohui C Ding Yu Y

FEBS open bio 20221009 12

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 ...[more]

PMID: 36176235

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Project description:CD137, a member of the tumor necrosis factor receptor superfamily of cell surface proteins, acts as a costimulatory receptor on T cells, natural killer cells, B cell subsets, and some dendritic cells. Agonistic anti-CD137 monoclonal antibody (MAb) therapy has been combined with other chemotherapeutic agents in human cancer trials. Based on its ability to promote tumor clearance, we hypothesized that anti-CD137 MAb might activate immune responses and resolve chronic viral infections. We evaluated anti-CD137 MAb therapy in a mouse infection model of chikungunya virus (CHIKV), an alphavirus that causes chronic polyarthritis in humans and is associated with reservoirs of CHIKV RNA that are not cleared efficiently by adaptive immune responses. Analysis of viral tropism revealed that CHIKV RNA was present preferentially in splenic B cells and follicular dendritic cells during the persistent phase of infection, and animals lacking B cells did not develop persistent CHIKV infection in lymphoid tissue. Anti-CD137 MAb treatment resulted in T cell-dependent clearance of CHIKV RNA in lymphoid tissue, although this effect was not observed in musculoskeletal tissue. The clearance of CHIKV RNA from lymphoid tissue by anti-CD137 MAb was associated with reductions in the numbers of germinal center B cells and follicular dendritic cells. Similar results were observed with anti-CD137 MAb treatment of mice infected with Mayaro virus, a related arthritogenic alphavirus. Thus, anti-CD137 MAb treatment promotes resolution of chronic alphavirus infection in lymphoid tissues by reducing the numbers of target cells for infection and persistence.IMPORTANCE Although CHIKV causes persistent infection in lymphoid and musculoskeletal tissues in multiple animals, the basis for this is poorly understood, which has hampered pharmacological efforts to promote viral clearance. Here, we evaluated the therapeutic effects on persistent CHIKV infection of an agonistic anti-CD137 MAb that can activate T cell and natural killer cell responses to clear tumors. We show that treatment with anti-CD137 MAb promotes the clearance of persistent alphavirus RNA from lymphoid but not musculoskeletal tissues. This occurs because anti-CD137 MAb-triggered T cells reduce the numbers of target germinal center B cells and follicular dendritic cells, which are the primary reservoirs for CHIKV in the spleen and lymph nodes. Our studies help to elucidate the basis for CHIKV persistence and begin to provide strategies that can clear long-term cellular reservoirs of infection.

Dataset Information

Development and characterization of a novel human CD137 agonistic antibody with anti-tumor activity and a good safety profile in non-human primates.

Publications

Development and characterization of a novel human CD137 agonistic antibody with anti-tumor activity and a good safety profile in non-human primates.

Similar Datasets

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