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ARS Home » Plains Area » Grand Forks, North Dakota » Grand Forks Human Nutrition Research Center » Dietary Prevention of Obesity-related Disease Research » Research » Publications at this Location » Publication #392183
Research Project: Modification of Diurnal Patterns to Promote Health in Models for Human Metabolic Dysfunction

Location: Dietary Prevention of Obesity-related Disease Research

Title: FSH–blocking therapeutic for osteoporosis and obesity

Author
item GERA, SAKSHI - The Icahn School Of Medicine At Mount Sinai
item KUO, TAN-CHUN - The Icahn School Of Medicine At Mount Sinai
item KORKMAZ, FUNDA - The Icahn School Of Medicine At Mount Sinai
item SANT, DAMINI - The Icahn School Of Medicine At Mount Sinai
item DEMAMBRO, VICTORIA - Maine Medical Center Research Institute (MMCRI)
item GUMEROVA, ANISA - The Icahn School Of Medicine At Mount Sinai
item SUDHA, KATHAYANI - The Icahn School Of Medicine At Mount Sinai
item PADILA, ASHLEY - The Icahn School Of Medicine At Mount Sinai
item PREVOT, GEOFFREY - The Icahn School Of Medicine At Mount Sinai
item MUNITZ, JAZZ - The Icahn School Of Medicine At Mount Sinai
item TEUNISSEN, ABRAHAM - The Icahn School Of Medicine At Mount Sinai
item VAN LEENT, MANDY - The Icahn School Of Medicine At Mount Sinai
item NETTO, JESSICA - The Icahn School Of Medicine At Mount Sinai
item SULTANA, FARHATH - The Icahn School Of Medicine At Mount Sinai
item SHELLY, ELEANOR - The Icahn School Of Medicine At Mount Sinai
item KUMAR, PUSHKAR - The Icahn School Of Medicine At Mount Sinai
item CULLEN, LAIM - The Icahn School Of Medicine At Mount Sinai
item CHATTERJEE, JIYA - The Icahn School Of Medicine At Mount Sinai
item MIYASHITA, SARI - The Icahn School Of Medicine At Mount Sinai
item KANNANGARA, HASI - The Icahn School Of Medicine At Mount Sinai
item BHONGADE, MEGHA - The Icahn School Of Medicine At Mount Sinai
item LEVLEVA, KSENIIA - The Icahn School Of Medicine At Mount Sinai
item MURADOVA, VALERIIA - The Icahn School Of Medicine At Mount Sinai
item BATISTA, ROGERIO - The Icahn School Of Medicine At Mount Sinai
item BOBINSON, CEMRE - The Icahn School Of Medicine At Mount Sinai
item MACDONALD, ANNE - The Icahn School Of Medicine At Mount Sinai
item BABUNOVIC, SUSAN - The Icahn School Of Medicine At Mount Sinai
item SAXENA, MANSI - The Icahn School Of Medicine At Mount Sinai
item MESECK, MARCIA - The Icahn School Of Medicine At Mount Sinai
item CAMINIS, JOHN - The Icahn School Of Medicine At Mount Sinai
item IQBAL, JAMEEL - The Icahn School Of Medicine At Mount Sinai
item NEW, MARIA - The Icahn School Of Medicine At Mount Sinai
item RYU, VITALY - The Icahn School Of Medicine At Mount Sinai
item KIM, SE-MIN - The Icahn School Of Medicine At Mount Sinai
item Cao, Jay
item ZAIDI, NEEHA - Sidney Kimmel Cancer Center
item FAYAD, ZAHI - The Icahn School Of Medicine At Mount Sinai
item LIZNEVA, DARIA - The Icahn School Of Medicine At Mount Sinai
item ROSEN, CLIFFORD - Maine Medical Center Research Institute (MMCRI)
item YUEN, TONY - The Icahn School Of Medicine At Mount Sinai
item ZAIDI, MONE - The Icahn School Of Medicine At Mount Sinai

Submitted to: eLife
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/14/2023
Publication Date: 9/20/2022
Citation: Gera, S., Kuo, T., Korkmaz, F., Sant, D., Demambro, V., Gumerova, A., Sudha, K., Padila, A., Prevot, G., Munitz, J., Teunissen, A., Van Leent, M., Netto, J., Sultana, F., Shelly, E., Kumar, P., Cullen, L., Chatterjee, J., Miyashita, S., Kannangara, H., Bhongade, M., Levleva, K., Muradova, V., Batista, R., Bobinson, C., Macdonald, A., Babunovic, S., Saxena, M., Meseck, M., Caminis, J., Iqbal, J., New, M.I., Ryu, V., Kim, S., Cao, J.J., Zaidi, N., Fayad, Z., Lizneva, D., Rosen, C.J., Yuen, T., Zaidi, M. 2022. FSH–blocking therapeutic for osteoporosis and obesity. eLife. 1-21. https://doi.org/10.7554/eLife.78022.
DOI: https://doi.org/10.7554/eLife.78022

Interpretive Summary: The risk of developing osteoporosis and obesity is increased right before and during menopause. Follicle stimulating hormone (FSH), a hormone produced by pituitary gland, may play an important role in regulating these two health disorders. This study examined how blocking FSH action with a monoclonal antibody affects bone metabolism and fat mass in mice and monkeys. We found that the antibody is safe in monkeys and inhibiting FSH with the antibody reduces fat mass and increases in bone mass.

Technical Abstract: Pharmacological and genetic studies over the past decade have established FSH as an actionable target for diseases affecting millions, notably osteoporosis, obesity and Alzheimer’s disease (AD). Blocking FSH action prevents bone loss, fat gain and AD–like features 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 obesity and 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, bone marrow and fat depots. MS-Hu6 displayed a ß phase t½ of 13 days (316 hours) in humanized Tg32 mice, and bound endogenous FSH. We tested 215 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 IFN' 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 as a multipurpose therapeutic.