First-in-class humanized FSH blocking antibody targets bone and fat.
Proc Natl Acad Sci U S A
; 117(46): 28971-28979, 2020 11 17.
Article
em En
| MEDLINE
| ID: mdl-33127753
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 FSHß 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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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Osso e Ossos
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Tecido Adiposo
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Anticorpos Bloqueadores
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Hormônio Foliculoestimulante
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Epitopos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2020
Tipo de documento:
Article