FSH-blocking therapeutic for osteoporosis
- Icahn School of Medicine at Mount Sinai, United States
- Maine Medical Center Research Institute, United States
- United States Department of Agriculture, United States
- Johns Hopkins University, United States
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 KD 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 89Zr-labelled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. MS-Hu6 displayed a β phase t½ 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 in silico 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file.
Article and author information
Author details
Funding
National Institute on Aging (R01 AG071870)
- Se-Min Kim
- Tony Yuen
- Mone Zaidi
National Institute on Aging (R01 AG074092)
- Tony Yuen
- Mone Zaidi
National Institute on Aging (U01 AG073148)
- Tony Yuen
- Mone Zaidi
National Institute on Aging (U19 AG060917)
- Clifford J Rosen
- Mone Zaidi
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK113627)
- Jameel Iqbal
- Mone Zaidi
National Institute of General Medical Sciences (P20 GM121301)
- Clifford J Rosen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (PROTO201900157) for non-human primate studies and (PROTO202100038) for mouse experiments at Icahn School of Medicine at Mount Sinai and at Maine Medical Center Research Institute.
Copyright
© 2022, Gera et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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FSH-blocking therapeutic for osteoporosis
eLife 11:e78022.
https://doi.org/10.7554/eLife.78022
Further reading
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- Medicine
This study investigates the effects of two parathyroid hormone (PTH) analogs, rhPTH(1-34) and dimeric R25CPTH(1-34), on bone regeneration and osseointegration in a postmenopausal osteoporosis model using beagle dogs. Twelve osteoporotic female beagles were subjected to implant surgeries and assigned to one of three groups: control, rhPTH(1-34), or dimeric R25CPTH(1-34). Bone regeneration and osseointegration were evaluated after 10 weeks using micro-computed tomographic (micro-CT), histological analyses, and serum biochemical assays. Results showed that the rhPTH(1-34) group demonstrated superior improvements in bone mineral density, trabecular architecture, and osseointegration compared to controls, while the dimeric R25CPTH(1-34) group exhibited similar, though slightly less pronounced, anabolic effects. Histological and TRAP assays indicated both PTH analogs significantly enhanced bone regeneration, especially in artificially created bone defects. The findings suggest that both rhPTH(1-34) and dimeric R25CPTH(1-34) hold potential as therapeutic agents for promoting bone regeneration and improving osseointegration around implants in osteoporotic conditions, with implications for their use in bone-related pathologies and reconstructive surgeries.
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- Medicine
- Neuroscience
Background:
Alcohol use disorder (AUD) is a global health problem with limited therapeutic options. The biochemical mechanisms that lead to this disorder are not yet fully understood, and in this respect, metabolomics represents a promising approach to decipher metabolic events related to AUD. The plasma metabolome contains a plethora of bioactive molecules that reflects the functional changes in host metabolism but also the impact of the gut microbiome and nutritional habits.
Methods:
In this study, we investigated the impact of severe AUD (sAUD), and of a 3-week period of alcohol abstinence, on the blood metabolome (non-targeted LC-MS metabolomics analysis) in 96 sAUD patients hospitalized for alcohol withdrawal.
Results:
We found that the plasma levels of different lipids ((lyso)phosphatidylcholines, long-chain fatty acids), short-chain fatty acids (i.e. 3-hydroxyvaleric acid) and bile acids were altered in sAUD patients. In addition, several microbial metabolites, including indole-3-propionic acid, p-cresol sulfate, hippuric acid, pyrocatechol sulfate, and metabolites belonging to xanthine class (paraxanthine, theobromine and theophylline) were sensitive to alcohol exposure and alcohol withdrawal. 3-Hydroxyvaleric acid, caffeine metabolites (theobromine, paraxanthine, and theophylline) and microbial metabolites (hippuric acid and pyrocatechol sulfate) were correlated with anxiety, depression and alcohol craving. Metabolomics analysis in postmortem samples of frontal cortex and cerebrospinal fluid of those consuming a high level of alcohol revealed that those metabolites can be found also in brain tissue.
Conclusions:
Our data allow the identification of neuroactive metabolites, from interactions between food components and microbiota, which may represent new targets arising in the management of neuropsychiatric diseases such as sAUD.
Funding:
Gut2Behave project was initiated from ERA-NET NEURON network (Joint Transnational Call 2019) and was financed by Academy of Finland, French National Research Agency (ANR-19-NEUR-0003-03) and the Fonds de la Recherche Scientifique (FRS-FNRS; PINT-MULTI R.8013.19, Belgium). Metabolomics analysis of the TSDS samples was supported by grant from the Finnish Foundation for Alcohol Studies.
