Gera, S; Sant, D; Haider, S; Korkmaz, F; Kuo, T-C; Mathew, M; Perez-Pena, H; ... Zaidi, M; + view all Gera, S; Sant, D; Haider, S; Korkmaz, F; Kuo, T-C; Mathew, M; Perez-Pena, H; Xie, H; Chen, H; Batista, R; Ma, K; Cheng, Z; Hadelia, E; Robinson, C; Macdonald, A; Miyashita, S; Williams, A; Jebian, G; Miyashita, H; Gumerova, A; Ievleva, K; Smith, P; He, J; Ryu, V; DeMambro, V; Quinn, MA; Meseck, M; Kim, S-M; Kumar, TR; Iqbal, J; New, MI; Lizneva, D; Rosen, CJ; Hsueh, AJ; Yuen, T; Zaidi, M; - view fewer (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.

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