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FSH-blocking therapeutic for osteoporosis.

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 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 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.

SUBMITTER: Gera S

PROVIDER: S-EPMC9550223 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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FSH-blocking therapeutic for osteoporosis.

Gera Sakshi S Kuo Tan-Chun TC Gumerova Anisa Azatovna AA Korkmaz Funda F Sant Damini D DeMambro Victoria V Sudha Karthyayani K Padilla Ashley A Prevot Geoffrey G Munitz Jazz J Teunissen Abraham A van Leent Mandy M T MMT Post Tomas G J M TGJM Fernandes Jessica C JC Netto Jessica J Sultana Farhath F Shelly Eleanor E Rojekar Satish S Kumar Pushkar P Cullen Liam L Chatterjee Jiya J Pallapati Anusha A Miyashita Sari S Kannangara Hasni H Bhongade Megha M Sengupta Puja P Ievleva Kseniia K Muradova Valeriia V Batista Rogerio R Robinson Cemre C Macdonald Anne A Hutchison Susan S Saxena Mansi M Meseck Marcia M Caminis John J Iqbal Jameel J New Maria I MI Ryu Vitaly V Kim Se-Min SM Cao Jay J JJ Zaidi Neeha N Fayad Zahi A ZA Lizneva Daria D Rosen Clifford J CJ Yuen Tony T Zaidi Mone M

eLife 20220920

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<sub>D</sub> of 7.52 nM. Using a Good Laboratory Practice (GLP)-compliant platform, we ...[more]

PMID: 36125123

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Project description:Highly concentrated antibody formulations are oftentimes required for subcutaneous, self-administered biologics. Here, we report the development of a unique formulation for our first-in-class FSH-blocking humanized antibody, MS-Hu6, which we propose to move to the clinic for osteoporosis, obesity, and Alzheimer's disease. The studies were carried out using our Good Laboratory Practice (GLP) platform, compliant with the Code of Federal Regulations (Title 21, Part 58). We first used protein thermal shift, size exclusion chromatography, and dynamic light scattering to examine MS-Hu6 concentrations between 1 and 100 mg/mL. We found that thermal, monomeric, and colloidal stability of formulated MS-Hu6 was maintained at a concentration of 100 mg/mL. The addition of the antioxidant L-methionine and chelating agent disodium EDTA improved the formulation's long-term colloidal and thermal stability. Thermal stability was further confirmed by Nano differential scanning calorimetry (DSC). Physiochemical properties of formulated MS-Hu6, including viscosity, turbidity, and clarity, confirmed with acceptable industry standards. That the structural integrity of MS-Hu6 in formulation was maintained was proven through Circular Dichroism (CD) and Fourier Transform Infrared (FTIR) Spectroscopy. Three rapid freeze-thaw cycles at -80 °C/25 °C or -80 °C/37 °C further revealed excellent thermal and colloidal stability. Furthermore, formulated MS-Hu6, particularly its Fab domain, displayed thermal and monomeric storage stability for more than 90 days at 4°C and 25°C. Finally, the unfolding temperature (Tm) for formulated MS-Hu6 increased by >4.80 °C upon binding to recombinant FSH, indicating highly specific ligand binding. Overall, we document the feasibility of developing a stable, manufacturable and transportable MS-Hu6 formulation at a ultra-high concentration at industry standards. The study should become a resource for developing biologic formulations in academic medical centers.

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FSH-blocking therapeutic for osteoporosis.

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FSH-blocking therapeutic for osteoporosis.

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