Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity
| العنوان: | Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity |
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| المؤلفون: | Douglas Burtrum, Helen Kotanides, Leyi Shen, Darin Chin, Ruslan D. Novosiadly, Amelie Forest, Rose Marie Sattler, Xinlei Chen, Yiwei Zhang, Michael Topper, David Surguladze, Jingxing Li, Jaafar N. Haidar, Ivan Inigo, Gregory D. Plowman, Colleen A. Burns, Lauren Boucher, Andreas Sonyi, Prachi Sharma, Michael Kalos, Dale L. Ludwig, Maria B. Lebron, Anthony Pennello, Carmine Carpenito, Juqun Shen |
| المصدر: | Molecular Cancer Therapeutics. 19:988-998 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Agonist, Cancer Research, Lung Neoplasms, medicine.drug_class, T cell, Apoptosis, Mice, SCID, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Monoclonal antibody, Epitope, Mice, Tumor Necrosis Factor Receptor Superfamily, Member 9, 03 medical and health sciences, 0302 clinical medicine, Immune system, Mice, Inbred NOD, Carcinoma, Non-Small-Cell Lung, Tumor Cells, Cultured, medicine, Animals, Humans, Receptor, Cell Proliferation, biology, Chemistry, CD137, NF-kappa B, Antibodies, Monoclonal, Xenograft Model Antitumor Assays, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, Antibody, Signal Transduction |
| الوصف: | The CD137 receptor plays a key role in mediating immune response by promoting T cell proliferation, survival, and memory. Effective agonism of CD137 has the potential to reinvigorate potent antitumor immunity either alone or in combination with other immune-checkpoint therapies. In this study, we describe the discovery and characterization of a unique CD137 agonist, 7A5, a fully human IgG1 Fc effector-null monoclonal antibody. The biological properties of 7A5 were investigated through in vitro and in vivo studies. 7A5 binds CD137, and the binding epitope overlaps with the CD137L binding site based on structure. 7A5 engages CD137 receptor and activates NF-κB cell signaling independent of cross-linking or Fc effector function. In addition, T cell activation measured by cytokine IFNγ production is induced by 7A5 in peripheral blood mononuclear cell costimulation assay. Human tumor xenograft mouse models reconstituted with human immune cells were used to determine antitumor activity in vivo. Monotherapy with 7A5 inhibits tumor growth, and this activity is enhanced in combination with a PD-L1 antagonist antibody. Furthermore, the intratumoral immune gene expression signature in response to 7A5 is highly suggestive of enhanced T cell infiltration and activation. Taken together, these results demonstrate 7A5 is a differentiated CD137 agonist antibody with biological properties that warrant its further development as a cancer immunotherapy. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc94399303b472e397241fa6366ca08f https://doi.org/10.1158/1535-7163.mct-19-0893 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bc94399303b472e397241fa6366ca08f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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