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 |
| Open access status: | An open access version is available from UCL Discovery |
| 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 > 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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