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

Sakshi Gera, Damini Sant, Shozeb Haider, Funda Korkmaz, Tan Chun Kuo, Mehr Mathew, Helena Perez-Pena, Honglin Xie, Hao Chen, Rogerio Batista, Kejun Ma, Zhen Cheng, Elina Hadelia, Cemre Robinson, Anne Macdonald, Sari Miyashita, Anthony Williams, Gregory Jebian, Hirotaka Miyashita, Anisa GumerovaKseniia Ievleva, Pinar Smith, Jiahuan He, Vitaly Ryu, Victoria DeMambro, Matthew A. Quinn, Marcia Meseck, Se Min Kim, T. Rajendra Kumar, Jameel Iqbal, Maria I. New, Daria Lizneva, Clifford J. Rosen, Aaron J. Hsueh, Tony Yuen, Mone Zaidi

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)28971-28979
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - 17 Nov 2020

Keywords

  • Monoclonal antibody | humanization | follicle-stimulating hormone | adipose

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