TY - JOUR
T1 - First-in-class humanized FSH blocking antibody targets bone and fat
AU - Gera, Sakshi
AU - Sant, Damini
AU - Haider, Shozeb
AU - Korkmaz, Funda
AU - Kuo, Tan Chun
AU - Mathew, Mehr
AU - Perez-Pena, Helena
AU - Xie, Honglin
AU - Chen, Hao
AU - Batista, Rogerio
AU - Ma, Kejun
AU - Cheng, Zhen
AU - Hadelia, Elina
AU - Robinson, Cemre
AU - Macdonald, Anne
AU - Miyashita, Sari
AU - Williams, Anthony
AU - Jebian, Gregory
AU - Miyashita, Hirotaka
AU - Gumerova, Anisa
AU - Ievleva, Kseniia
AU - Smith, Pinar
AU - He, Jiahuan
AU - Ryu, Vitaly
AU - DeMambro, Victoria
AU - Quinn, Matthew A.
AU - Meseck, Marcia
AU - Kim, Se Min
AU - Rajendra Kumar, T.
AU - Iqbal, Jameel
AU - New, Maria I.
AU - Lizneva, Daria
AU - Rosen, Clifford J.
AU - Hsueh, Aaron J.
AU - Yuen, Tony
AU - Zaidi, Mone
N1 - Funding Information:
ACKNOWLEDGMENTS. M.Z. is grateful to the National Institutes of Health for grant support, namely U19 AG60917 (to M.Z. and C.J.R.) and R01 DK113627 (to M.Z.). M.I.N. is supported by the Maria I. New Children’s Hormone Research Foundation. M.Z. is an inventor on patents on FSH, bone, and body fat regulation. These patents are owned by Icahn School of Medicine at Mount Sinai, with M.Z. being a recipient of royalties should they arise per institutional policies. M.Z. also consults for several financial platforms, including Gerson Lehrman Group and Guidepoint, on drugs for osteoporosis and genetic bone diseases.
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
PY - 2020/11/17
Y1 - 2020/11/17
N2 - 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.
AB - 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.
KW - Monoclonal antibody | humanization | follicle-stimulating hormone | adipose
UR - http://www.scopus.com/inward/record.url?scp=85096364565&partnerID=8YFLogxK
U2 - 10.1073/pnas.2014588117
DO - 10.1073/pnas.2014588117
M3 - Article
C2 - 33127753
AN - SCOPUS:85096364565
VL - 117
SP - 28971
EP - 28979
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 46
ER -