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 Gumerova; Kseniia 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

doi:10.1073/pnas.2014588117

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

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33 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 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.

Original language	English
Pages (from-to)	28971-28979
Number of pages	9
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	117
Issue number	46
DOIs	https://doi.org/10.1073/pnas.2014588117
State	Published - 17 Nov 2020

Keywords

Monoclonal antibody | humanization | follicle-stimulating hormone | adipose

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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., ... Zaidi, M. (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), 28971-28979. https://doi.org/10.1073/pnas.2014588117

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title = "First-in-class humanized FSH blocking antibody targets bone and fat",

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.",

keywords = "Monoclonal antibody | humanization | follicle-stimulating hormone | adipose",

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

year = "2020",

month = nov,

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doi = "10.1073/pnas.2014588117",

language = "English",

volume = "117",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Gera, S, Sant, D, Haider, S, Korkmaz, F, Kuo, TC, 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, SM, Rajendra Kumar, T, Iqbal, J, New, MI, Lizneva, D, Rosen, CJ, Hsueh, AJ, Yuen, T & Zaidi, M 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, vol. 117, no. 46, pp. 28971-28979. https://doi.org/10.1073/pnas.2014588117

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

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

SN - 0027-8424

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

IS - 46

ER -

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

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Keywords

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