FSH-blocking therapeutic for osteoporosis
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Curated by eLife
Evaluation Summary:
The authors describe a comprehensive characterization of a new humanized FSH blocking antibody (MS-Hu6), which they have studied in-depth in terms of its efficacy on bone and fat tissues. They provide compelling data on mouse and monkey species with a complete evaluation of its pharmacokinetics and biodistribution and characterize its effect for the treatment of obesity and bone loss. It is an important contribution and will be useful to a general readership in endocrinology, bone and fat metabolism.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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 D of 7.52 nM. Using a Good Laboratory Practice (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 89 Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a β phase t ½ of 7.5 days (180 hr) 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. The MS-Hu6 showed the same level of “humanness” as human IgG1 in silico and was non-immunogenic in ELISpot assays for IL-2 and IFN-γ 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.
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Evaluation Summary:
The authors describe a comprehensive characterization of a new humanized FSH blocking antibody (MS-Hu6), which they have studied in-depth in terms of its efficacy on bone and fat tissues. They provide compelling data on mouse and monkey species with a complete evaluation of its pharmacokinetics and biodistribution and characterize its effect for the treatment of obesity and bone loss. It is an important contribution and will be useful to a general readership in endocrinology, bone and fat metabolism.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Obesity and osteopenia are hallmarks of post-menopause culminating with osteoporosis if not treated with hormone replacement therapy. FSH is a sex hormone that regulates estrogen, however, the rising levels of FSH during pre- and post-menopause are implicated in obesity and osteoporosis The authors find that the FSH blocking antibody reduces body fat in mice on a high-fat diet and induces beige, UCP1-rich adipose tissue. The antibody also increases bone formation in mice to display an anabolic action evident in histomorphometry and an increase in bone mass. This dataset has been reproduced in a different lab in mice that had been ovariectomized and had lost bone. The authors also perform multipronged pharmacokinetic studies using mice with different genetic backgrounds and different technologies for …
Reviewer #1 (Public Review):
Obesity and osteopenia are hallmarks of post-menopause culminating with osteoporosis if not treated with hormone replacement therapy. FSH is a sex hormone that regulates estrogen, however, the rising levels of FSH during pre- and post-menopause are implicated in obesity and osteoporosis The authors find that the FSH blocking antibody reduces body fat in mice on a high-fat diet and induces beige, UCP1-rich adipose tissue. The antibody also increases bone formation in mice to display an anabolic action evident in histomorphometry and an increase in bone mass. This dataset has been reproduced in a different lab in mice that had been ovariectomized and had lost bone. The authors also perform multipronged pharmacokinetic studies using mice with different genetic backgrounds and different technologies for detection of the injected antibody. These studies were coupled with biodistribution studies both in mice and monkeys showing that the antibody reaches the organs of interest. The monkeys were also used for a preliminary safety assessment, and the authors also assessed immunogenicity using human PBMCs. Finally, to facilitate future clinical development, the authors have used traditional biochemical measures combined with a thorough in silico analysis to establish that the antibody can be manufactured.
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Reviewer #2 (Public Review):
During the late perimenopause, there is precipitous bone loss, onset of visceral obesity, dysregulated energy balance, and reduced physical activity. These aberrant physiologic changes across the menopausal transition are not fully explained by low estrogen, as estrogen levels are relatively unperturbed, while serum FSH levels rise to maintain estrogen secretion from an otherwise failing ovary. The question has been whether a rising FSH level is a driver for post-menopausal obesity and osteoporosis. The objective of the study is to test whether blocking FSH action will reduce obesity and bone loss in people. Towards this goal, the authors have developed our lead candidate, a first-in-class humanized FSH-blocking antibody, MS-Hu6. Obesity and osteoporosis are major public health problems. These two disorders …
Reviewer #2 (Public Review):
During the late perimenopause, there is precipitous bone loss, onset of visceral obesity, dysregulated energy balance, and reduced physical activity. These aberrant physiologic changes across the menopausal transition are not fully explained by low estrogen, as estrogen levels are relatively unperturbed, while serum FSH levels rise to maintain estrogen secretion from an otherwise failing ovary. The question has been whether a rising FSH level is a driver for post-menopausal obesity and osteoporosis. The objective of the study is to test whether blocking FSH action will reduce obesity and bone loss in people. Towards this goal, the authors have developed our lead candidate, a first-in-class humanized FSH-blocking antibody, MS-Hu6. Obesity and osteoporosis are major public health problems. These two disorders track together in women across the menopausal transition. The study provided that MS-Hu6 is efficacious, durable and manufacturable, and is therefore poised for future human testing as a multipurpose therapeutic. It is a thorough characterization of MS-Hu6 in vivo efficacy, acute safety in monkeys, and a full evaluation of its pharmacokinetic, pharmacodynamic and biodistribution. This comprehensive analysis of the biology and physicochemistry is a first-in-class, humanized FSH- blocking antibody.
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