FSH-blocking therapeutic for osteoporosis

Author:

Gera Sakshi1ORCID,Kuo Tan-Chun1ORCID,Gumerova Anisa Azatovna1,Korkmaz Funda1,Sant Damini1,DeMambro Victoria2,Sudha Karthyayani1,Padilla Ashley1,Prevot Geoffrey3,Munitz Jazz3,Teunissen Abraham3ORCID,van Leent Mandy MT3,Post Tomas GJM3,Fernandes Jessica C3,Netto Jessica1,Sultana Farhath1,Shelly Eleanor1,Rojekar Satish1,Kumar Pushkar1,Cullen Liam1,Chatterjee Jiya1,Pallapati Anusha1,Miyashita Sari1,Kannangara Hasni1,Bhongade Megha1,Sengupta Puja1,Ievleva Kseniia1,Muradova Valeriia1,Batista Rogerio1,Robinson Cemre1,Macdonald Anne1,Hutchison Susan1,Saxena Mansi4,Meseck Marcia14,Caminis John1,Iqbal Jameel1,New Maria I1,Ryu Vitaly1ORCID,Kim Se-Min1,Cao Jay J5,Zaidi Neeha6,Fayad Zahi A3,Lizneva Daria1,Rosen Clifford J2ORCID,Yuen Tony1,Zaidi Mone1ORCID

Affiliation:

1. Center for Translational Medicine and Pharmacology and The Mount Sinai Bone Program, Departments of Medicine and of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai

2. Maine Medical Center Research Institute

3. BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai

4. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai

5. United States Department of Agriculture, Grand Forks Human Nutrition Research Center

6. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University

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 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 89Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a β phase t½ 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.

Funder

National Institute on Aging

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute of General Medical Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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