FSH-blocking therapeutic for osteoporosis.

Autor:	Gera S; 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, New York, United States., Kuo TC; 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, New York, United States., Gumerova AA; 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, New York, United States., Korkmaz F; 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, New York, United States., Sant D; 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, New York, United States., DeMambro V; Maine Medical Center Research Institute, Scarborough, United States., Sudha K; 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, New York, United States., Padilla A; 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, New York, United States., Prevot G; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Munitz J; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Teunissen A; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States., van Leent MMT; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Post TGJM; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Fernandes JC; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Netto J; 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, New York, United States., Sultana F; 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, New York, United States., Shelly E; 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, New York, United States., Rojekar S; 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, New York, United States., Kumar P; 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, New York, United States., Cullen L; 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, New York, United States., Chatterjee J; 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, New York, United States., Pallapati A; 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, New York, United States., Miyashita S; 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, New York, United States., Kannangara H; 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, New York, United States., Bhongade M; 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, New York, United States., Sengupta P; 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, New York, United States., Ievleva K; 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, New York, United States., Muradova V; 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, New York, United States., Batista R; 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, New York, United States., Robinson C; 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, New York, United States., Macdonald A; 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, New York, United States., Hutchison S; 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, New York, United States., Saxena M; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Meseck M; 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, New York, United States.; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Caminis J; 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, New York, United States., Iqbal J; 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, New York, United States., New MI; 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, New York, United States., Ryu V; 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, New York, United States., Kim SM; 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, New York, United States., Cao JJ; United States Department of Agriculture, Grand Forks Human Nutrition Research Center, Grand Forks, United States., Zaidi N; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, United States., Fayad ZA; BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States., Lizneva D; 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, New York, United States., Rosen CJ; Maine Medical Center Research Institute, Scarborough, United States., Yuen T; 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, New York, United States., Zaidi M; 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, New York, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Sep 20; Vol. 11. Date of Electronic Publication: 2022 Sep 20.
DOI:	10.7554/eLife.78022
Abstrakt:	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. Competing Interests: SG, TK, AG, FK, DS, VD, KS, AP, GP, JM, AT, Mv, TP, JF, JN, FS, ES, SR, PK, LC, JC, AP, SM, HK, MB, PS, KI, VM, RB, CR, AM, SH, MS, MM, JC, MN, VR, SK, JC, NZ, ZF, DL, CR No competing interests declared, JI, TY Reviewing editor, eLife, MZ is an inventor on issued patents on inhibiting FSH for the prevention and treatment of osteoporosis and obesity (U.S. Patent 8,435,948 and 11,034,761). M.Z. is also an inventor on pending patent application on composition and use of humanized monoclonal anti-FSH antibodies, and is co-inventor of a pending patent on the use of FSH as a target for preventing Alzheimer's disease. These patents are owned by Icahn School of Medicine at Mount Sinai (ISMMS), and M.Z. would be recipient of royalties, per institutional policy. M.Z. also consults for several financial platforms, including Gerson Lehman Group and Guidepoint, on drugs for osteoporosis and genetic bone diseases. Deputy editor, eLife (© 2022, Gera, Kuo, Gumerova et al.)
Databáze:	MEDLINE
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