Open AccessFirst-in-class humanized FSH blocking antibody targets bone and fat
Author(s) -
Sakshi Gera,
Damini Sant,
Shozeb Haider,
Funda Korkmaz,
Tan-Chun Kuo,
Mehr Mathew,
Helena Perez-Pena,
Hai Xie,
Hao Chen,
Rogerio Batista,
M. A. Knepper,
Zhen Cheng,
Elina Hadelia,
Cemre Robinson,
Anne Macdonald,
Sari Miyashita,
Angie Williams,
Gregory Jebian,
Hirotaka Miyashita,
Anisa Gumerova,
Kseniia Ievleva,
Pinar J. Smith,
Jianyong He,
Vitaly Ryu,
Victoria DeMambro,
Matthew Quinn,
Marcia Meseck,
Semin Kim,
T. Rajendra Kumar,
Jameel Iqbal,
Maria I. New,
Daria Lizneva,
Clifford J. Rosen,
Aaron J. W. Hsueh,
Tony Yuen,
Mone Zaidi
Publication year - 2020
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2014588117
Subject(s) - follicle stimulating hormone receptor , endocrinology , follicle stimulating hormone , antibody , medicine , osteoporosis , hormone , receptor , adipogenesis , adipose tissue , immunology , luteinizing hormone
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 K D 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.