FSH-blocking therapeutic for osteoporosis

Authors

Sakshi Gera, Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States.
Tan-Chun Kuo, Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States.
Anisa Azatovna Gumerova, Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States.
Funda Korkmaz, Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States.
Damini Sant, Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States.
Victoria DeMambro, Maine Medical Center
Karthyayani Sudha, Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States.
Ashley Padilla, Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States.
Geoffrey Prevot, BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States.
Jazz Munitz, BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States.
Abraham Teunissen, BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States.

Document Type

Article

Publication Date

9-20-2022

Institution/Department

MaineHealth Institute for Research

Journal Title

eLife

Abstract

Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions, namely osteoporosis, obesity, and Alzheimer's disease. Blocking FSH action prevents bone loss, fat gain and neurodegeneration in mice. We recently developed a first-in-class, humanized, epitope-specific FSH-blocking antibody, MS-Hu6, with a K of 7.52 nM. Using a GLP-compliant platform, we now report the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice and parameters of acute safety in monkeys. Biodistribution studies using Zr-labelled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. MS-Hu6 displayed a β phase t of 7.5 days (180 hours) in humanized Tg32 mice. We tested 217 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze-thaw and at different temperatures, with minimal aggregation, and without self-, cross-, or hydrophobic interactions or appreciable binding to relevant human antigens. MS-Hu6 showed the same level of 'humanness' as human IgG1 and was non-immunogenic in ELISPOT assays for IL-2 and IFNg in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable, and manufacturable, and is therefore poised for future human testing.

Recommended Citation

Gera S, Kuo TC, Gumerova AA, et al. FSH-blocking therapeutic for osteoporosis [published online ahead of print, 2022 Sep 20]. Elife. 2022;11:e78022. doi:10.7554/eLife.78022