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 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-labelled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. MS-Hu6 displayed a β phase t½ of 7.5 days (180 hours) 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. MS-Hu6 showed the same level of 'humanness' as human IgG1 in silico and was non-immunogenic in ELISPOT assays for IL-2 and IFNg 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Sakshi Gera

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1615-6259
  2. Tan-Chun Kuo

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5301-755X
  3. Anisa Azatovna Gumerova

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  4. Funda Korkmaz

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  5. Damini Sant

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  6. Victoria DeMambro

    Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    No competing interests declared.
  7. Karthyayani Sudha

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  8. Ashley Padilla

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  9. Geoffrey Prevot

    BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  10. Jazz Munitz

    BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  11. Abraham Teunissen

    BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0401-8262
  12. Mandy MT van Leent

    BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  13. Tomas GJM Post

    BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  14. Jessica C Fernandes

    BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  15. Jessica Netto

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  16. Farhath Sultana

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  17. Eleanor Shelly

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  18. Satish Rojekar

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  19. Pushkar Kumar

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  20. Liam Cullen

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  21. Jiya Chatterjee

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  22. Anusha Pallapati

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  23. Sari Miyashita

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  24. Hasni Kannangara

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  25. Megha Bhongade

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  26. Puja Sengupta

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  27. Kseniia Ievleva

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  28. Valeriia Muradova

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  29. Rogerio Batista

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  30. Cemre Robinson

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  31. Anne Macdonald

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  32. Susan Babunovic

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  33. Mansi Saxena

    Tisch Cancer Institu, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  34. Marcia Meseck

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  35. John Caminis

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  36. Jameel Iqbal

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    Jameel Iqbal, Reviewing editor, eLife.
  37. Maria I New

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  38. Vitaly Ryu

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8068-4577
  39. Se-Min Kim

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  40. Jay J Cao

    Grand Forks Human Nutrition Research Center, United States Department of Agriculture, Grand Forks, United States
    Competing interests
    No competing interests declared.
  41. Neeha Zaidi

    Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  42. Zahi A Fayad

    BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  43. Daria Lizneva

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    No competing interests declared.
  44. Clifford J Rosen

    Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3436-8199
  45. Tony Yuen

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    Tony.yuen@mountsinai.org
    Competing interests
    Tony Yuen, Reviewing editor, eLife.
  46. Mone Zaidi

    Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, United States
    For correspondence
    mone.zaidi@mountsinai.org
    Competing interests
    Mone Zaidi, 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5911-9522

Funding

National Institute on Aging (R01 AG071870)

  • Se-Min Kim
  • Tony Yuen
  • Mone Zaidi

National Institute on Aging (R01 AG074092)

  • Tony Yuen
  • Mone Zaidi

National Institute on Aging (U01 AG073148)

  • Tony Yuen
  • Mone Zaidi

National Institute on Aging (U19 AG060917)

  • Clifford J Rosen
  • Mone Zaidi

National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK113627)

  • Jameel Iqbal
  • Mone Zaidi

National Institute of General Medical Sciences (P20 GM121301)

  • Clifford J Rosen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (PROTO201900157) for non-human primate studies and (PROTO202100038) for mouse experiments at Icahn School of Medicine at Mount Sinai and at Maine Medical Center Research Institute.

Reviewing Editor

  1. Yousef Abu-Amer, Washington University Medical Center, United States

Publication history

  1. Received: February 19, 2022
  2. Accepted: September 14, 2022
  3. Accepted Manuscript published: September 20, 2022 (version 1)

Copyright

© 2022, Gera et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sakshi Gera
  2. Tan-Chun Kuo
  3. Anisa Azatovna Gumerova
  4. Funda Korkmaz
  5. Damini Sant
  6. Victoria DeMambro
  7. Karthyayani Sudha
  8. Ashley Padilla
  9. Geoffrey Prevot
  10. Jazz Munitz
  11. Abraham Teunissen
  12. Mandy MT van Leent
  13. Tomas GJM Post
  14. Jessica C Fernandes
  15. Jessica Netto
  16. Farhath Sultana
  17. Eleanor Shelly
  18. Satish Rojekar
  19. Pushkar Kumar
  20. Liam Cullen
  21. Jiya Chatterjee
  22. Anusha Pallapati
  23. Sari Miyashita
  24. Hasni Kannangara
  25. Megha Bhongade
  26. Puja Sengupta
  27. Kseniia Ievleva
  28. Valeriia Muradova
  29. Rogerio Batista
  30. Cemre Robinson
  31. Anne Macdonald
  32. Susan Babunovic
  33. Mansi Saxena
  34. Marcia Meseck
  35. John Caminis
  36. Jameel Iqbal
  37. Maria I New
  38. Vitaly Ryu
  39. Se-Min Kim
  40. Jay J Cao
  41. Neeha Zaidi
  42. Zahi A Fayad
  43. Daria Lizneva
  44. Clifford J Rosen
  45. Tony Yuen
  46. Mone Zaidi
(2022)
FSH-blocking therapeutic for osteoporosis
eLife 11:e78022.
https://doi.org/10.7554/eLife.78022

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    Conclusions:

    Therapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1β/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC.

    Funding:

    Supported by KL2 career development grant by Miami CTSI under NIH Award UL1TR002736, Stanley Glaser Foundation, American College of Surgeons Franklin Martin Career Development Award, and Association for Academic Surgery Joel J. Roslyn Faculty Award (to J. Datta); NIH R01 CA161976 (to N.B. Merchant); and NCI/NIH Award P30CA240139 (to J. Datta and N.B. Merchant).

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