Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism.

Autor:	He C; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA., Maniyar RR; Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Avraham Y; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Zappasodi R; Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Medicine, New York, NY, USA.; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY, USA., Rusinova R; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA., Newman W; Leap Therapeutics, Cambridge, MA, USA., Heath H; Leap Therapeutics, Cambridge, MA, USA., Wolchok JD; Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Medicine, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Dahan R; Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel., Merghoub T; Ludwig Collaborative and Swim Across America Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Weill Cornell Medicine, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Meyerson JR; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2022 Feb 25; Vol. 8 (8), pp. eabm4552. Date of Electronic Publication: 2022 Feb 25.
DOI:	10.1126/sciadv.abm4552
Abstrakt:	GITR is a TNF receptor, and its activation promotes immune responses and drives antitumor activity. The receptor is activated by the GITR ligand (GITRL), which is believed to cluster receptors into a high-order array. Immunotherapeutic agonist antibodies also activate the receptor, but their mechanisms are not well characterized. We solved the structure of full-length mouse GITR bound to Fabs from the antibody DTA-1. The receptor is a dimer, and each subunit binds one Fab in an orientation suggesting that the antibody clusters receptors. Binding experiments with purified proteins show that DTA-1 IgG and GITRL both drive extensive clustering of GITR. Functional data reveal that DTA-1 and the anti-human GITR antibody TRX518 activate GITR in their IgG forms but not as Fabs. Thus, the divalent character of the IgG agonists confers an ability to mimic GITRL and cluster and activate GITR. These findings will inform the clinical development of this class of antibodies for immuno-oncology.
Databáze:	MEDLINE
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