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First-in-class humanized FSH blocking antibody targets bone and fat

Gera, S; Sant, D; Haider, S; Korkmaz, F; Kuo, T-C; Mathew, M; Perez-Pena, H; ... Zaidi, M; + view all (2020) First-in-class humanized FSH blocking antibody targets bone and fat. Proceedings of the National Academy of Sciences of the United States of America , 117 (46) pp. 28971-28979. 10.1073/pnas.2014588117.

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Abstract

Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing.

Type: Article
Title: First-in-class humanized FSH blocking antibody targets bone and fat
Location: United States
DOI: 10.1073/pnas.2014588117
Publisher version: http://dx.doi.org/10.1073/pnas.2014588117
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: adipose, follicle-stimulating hormone, humanization, monoclonal antibody
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10115406
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