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FSH-blocking therapeutic for osteoporosis
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550223/ https://www.ncbi.nlm.nih.gov/pubmed/36125123 http://dx.doi.org/10.7554/eLife.78022 |
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author | Gera, Sakshi Kuo, Tan-Chun Gumerova, Anisa Azatovna Korkmaz, Funda Sant, Damini DeMambro, Victoria Sudha, Karthyayani Padilla, Ashley Prevot, Geoffrey Munitz, Jazz Teunissen, Abraham van Leent, Mandy MT Post, Tomas GJM Fernandes, Jessica C Netto, Jessica Sultana, Farhath Shelly, Eleanor Rojekar, Satish Kumar, Pushkar Cullen, Liam Chatterjee, Jiya Pallapati, Anusha Miyashita, Sari Kannangara, Hasni Bhongade, Megha Sengupta, Puja Ievleva, Kseniia Muradova, Valeriia Batista, Rogerio Robinson, Cemre Macdonald, Anne Hutchison, Susan Saxena, Mansi Meseck, Marcia Caminis, John Iqbal, Jameel New, Maria I Ryu, Vitaly Kim, Se-Min Cao, Jay J Zaidi, Neeha Fayad, Zahi A Lizneva, Daria Rosen, Clifford J Yuen, Tony Zaidi, Mone |
author_facet | Gera, Sakshi Kuo, Tan-Chun Gumerova, Anisa Azatovna Korkmaz, Funda Sant, Damini DeMambro, Victoria Sudha, Karthyayani Padilla, Ashley Prevot, Geoffrey Munitz, Jazz Teunissen, Abraham van Leent, Mandy MT Post, Tomas GJM Fernandes, Jessica C Netto, Jessica Sultana, Farhath Shelly, Eleanor Rojekar, Satish Kumar, Pushkar Cullen, Liam Chatterjee, Jiya Pallapati, Anusha Miyashita, Sari Kannangara, Hasni Bhongade, Megha Sengupta, Puja Ievleva, Kseniia Muradova, Valeriia Batista, Rogerio Robinson, Cemre Macdonald, Anne Hutchison, Susan Saxena, Mansi Meseck, Marcia Caminis, John Iqbal, Jameel New, Maria I Ryu, Vitaly Kim, Se-Min Cao, Jay J Zaidi, Neeha Fayad, Zahi A Lizneva, Daria Rosen, Clifford J Yuen, Tony Zaidi, Mone |
author_sort | Gera, Sakshi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9550223 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-95502232022-10-11 FSH-blocking therapeutic for osteoporosis Gera, Sakshi Kuo, Tan-Chun Gumerova, Anisa Azatovna Korkmaz, Funda Sant, Damini DeMambro, Victoria Sudha, Karthyayani Padilla, Ashley Prevot, Geoffrey Munitz, Jazz Teunissen, Abraham van Leent, Mandy MT Post, Tomas GJM Fernandes, Jessica C Netto, Jessica Sultana, Farhath Shelly, Eleanor Rojekar, Satish Kumar, Pushkar Cullen, Liam Chatterjee, Jiya Pallapati, Anusha Miyashita, Sari Kannangara, Hasni Bhongade, Megha Sengupta, Puja Ievleva, Kseniia Muradova, Valeriia Batista, Rogerio Robinson, Cemre Macdonald, Anne Hutchison, Susan Saxena, Mansi Meseck, Marcia Caminis, John Iqbal, Jameel New, Maria I Ryu, Vitaly Kim, Se-Min Cao, Jay J Zaidi, Neeha Fayad, Zahi A Lizneva, Daria Rosen, Clifford J Yuen, Tony Zaidi, Mone eLife Medicine 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. eLife Sciences Publications, Ltd 2022-09-20 /pmc/articles/PMC9550223/ /pubmed/36125123 http://dx.doi.org/10.7554/eLife.78022 Text en © 2022, Gera, Kuo, Gumerova et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Medicine Gera, Sakshi Kuo, Tan-Chun Gumerova, Anisa Azatovna Korkmaz, Funda Sant, Damini DeMambro, Victoria Sudha, Karthyayani Padilla, Ashley Prevot, Geoffrey Munitz, Jazz Teunissen, Abraham van Leent, Mandy MT Post, Tomas GJM Fernandes, Jessica C Netto, Jessica Sultana, Farhath Shelly, Eleanor Rojekar, Satish Kumar, Pushkar Cullen, Liam Chatterjee, Jiya Pallapati, Anusha Miyashita, Sari Kannangara, Hasni Bhongade, Megha Sengupta, Puja Ievleva, Kseniia Muradova, Valeriia Batista, Rogerio Robinson, Cemre Macdonald, Anne Hutchison, Susan Saxena, Mansi Meseck, Marcia Caminis, John Iqbal, Jameel New, Maria I Ryu, Vitaly Kim, Se-Min Cao, Jay J Zaidi, Neeha Fayad, Zahi A Lizneva, Daria Rosen, Clifford J Yuen, Tony Zaidi, Mone FSH-blocking therapeutic for osteoporosis |
title | FSH-blocking therapeutic for osteoporosis |
title_full | FSH-blocking therapeutic for osteoporosis |
title_fullStr | FSH-blocking therapeutic for osteoporosis |
title_full_unstemmed | FSH-blocking therapeutic for osteoporosis |
title_short | FSH-blocking therapeutic for osteoporosis |
title_sort | fsh-blocking therapeutic for osteoporosis |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9550223/ https://www.ncbi.nlm.nih.gov/pubmed/36125123 http://dx.doi.org/10.7554/eLife.78022 |
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