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

Sakshi Gera1, Damini Sant1, Shozeb Haider2

  • 1The Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

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A novel antibody blocks follicle-stimulating hormone (FSH) action, potentially treating obesity, high cholesterol, and osteoporosis. This antibody shows promise for developing new therapies against these widespread health issues.

Keywords:
adiposefollicle-stimulating hormonehumanizationmonoclonal antibody

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Area of Science:

  • Endocrinology and Reproductive Biology
  • Immunology and Therapeutics

Background:

  • Follicle-stimulating hormone (FSH) plays a role in regulating body fat, cholesterol levels, and bone mass.
  • Genetic or pharmacological blockade of FSH in mice has demonstrated positive effects on these metabolic and skeletal parameters.
  • These findings suggest that targeting FSH could offer a therapeutic strategy for obesity, hypercholesterolemia, and osteoporosis.

Purpose of the Study:

  • To develop and characterize a novel, fully humanized antibody capable of blocking FSH activity.
  • To investigate the binding mechanism and functional consequences of this FSH-blocking antibody.

Main Methods:

  • Generation of a first-in-class, fully humanized, epitope-specific FSH blocking antibody.
  • Structural and functional analyses including protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface.
  • Assessment of antibody binding affinity (KD of 7 nM) and its effect on FSH receptor interaction.

Main Results:

  • The humanized antibody demonstrated stable binding to key residues (two of five) at the FSHβ subunit-receptor interface.
  • This binding was sufficient to effectively block the interaction between FSH and its receptor.
  • The antibody profoundly inhibited FSH action in cell-based assays.

Conclusions:

  • A novel, fully humanized antibody has been developed that specifically blocks FSH action by interfering with receptor binding.
  • This antibody represents a promising first-in-class therapeutic candidate for obesity, hypercholesterolemia, and osteoporosis.
  • Further preclinical and clinical testing is warranted to evaluate its therapeutic potential.