학술논문
M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.
Document Type
Academic Journal
Author
Xu C; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Zhou X; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Webb L; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Yalavarthi S; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Zheng W; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Saha S; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Schweickhardt R; Discovery and Development Technologies, EMD Serono, Billerica, Massachusetts.; Soloviev M; Discovery and Development Technologies, EMD Serono, Billerica, Massachusetts.; Jenkins MH; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Brandstetter S; The Healthcare Business of Merck KGaA, Darmstadt, Germany.; Belousova N; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Alimzhanov M; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Rabinovich B; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Deshpande AM; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.; Brewis N; F-star Therapeutics, Cambridge, United Kingdom.; Helming L; Research Unit Oncology, EMD Serono, Billerica, Massachusetts.
Source
Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101614637 Publication Model: Print Cited Medium: Internet ISSN: 2326-6074 (Electronic) Linking ISSN: 23266066 NLM ISO Abbreviation: Cancer Immunol Res Subsets: MEDLINE
Subject
Language
English
Abstract
The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.
(©2023 American Association for Cancer Research.)
(©2023 American Association for Cancer Research.)