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

Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28971-28979. doi: 10.1073/pnas.2014588117. Epub 2020 Oct 30.

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: adipose; follicle-stimulating hormone; humanization; monoclonal antibody.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Animals
  • Antibodies, Blocking / chemistry
  • Antibodies, Blocking / immunology*
  • Antibodies, Monoclonal
  • Bone Density
  • Bone and Bones / metabolism*
  • Epitopes*
  • Female
  • Follicle Stimulating Hormone / chemistry
  • Follicle Stimulating Hormone / immunology*
  • Follicle Stimulating Hormone, beta Subunit / immunology
  • Humans
  • Hypercholesterolemia
  • Mice
  • Mice, Inbred C57BL
  • Molecular Dynamics Simulation
  • Obesity
  • Osteoporosis
  • Receptors, FSH / metabolism

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Epitopes
  • Follicle Stimulating Hormone, beta Subunit
  • Receptors, FSH
  • Follicle Stimulating Hormone