First-in-class humanized FSH blocking antibody targets bone and fat
Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, struc...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 46; pp. 28971 - 28979 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
17.11.2020
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 1091-6490 |
| DOI | 10.1073/pnas.2014588117 |
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| Abstract | Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a K
D of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH–FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing. |
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| AbstractList | We report the development and characterization of a first-in-class humanized antibody to follicle-stimulating hormone (FSH). We have shown previously that blocking FSH action on its receptor increases bone mass, reduces body fat, and enhances energy expenditure. Furthermore, FSH has been reported to increase serum cholesterol. Therefore, an anti-FSH agent has the potential of preventing and treating obesity, osteoporosis, and hypercholesterolemia, diseases that affect millions of women and men worldwide. Our study provides the framework for further preclinical and subsequent clinical testing of our humanized antibody to FSH.
Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a
K
D
of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH–FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing. Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a K D of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH–FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing. Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing. Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing.Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing. Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a KD of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH–FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing. |
| Author | Korkmaz, Funda Sant, Damini Ma, Kejun Ievleva, Kseniia Kumar, T. Rajendra Miyashita, Hirotaka Gumerova, Anisa Mathew, Mehr Robinson, Cemre Batista, Rogerio Ryu, Vitaly Zaidi, Mone Kuo, Tan-Chun He, Jiahuan Quinn, Matthew A. Iqbal, Jameel Xie, Honglin Haider, Shozeb Chend, Hao Hadelia, Elina Lizneva, Daria Rosen, Clifford J. Miyashita, Sari Yuen, Tony Gera, Sakshi Perez-Pena, Helena DeMambro, Victoria New, Maria I. Hsueh, Aaron J. Cheng, Zhen Jebian, Gregory Smith, Pinar Williams, Anthony Macdonald, Anne Meseck, Marcia Kim, Se-Min |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33127753$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright National Academy of Sciences Nov 17, 2020 2020 |
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| Keywords | adipose follicle-stimulating hormone monoclonal antibody humanization |
| Language | English |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Reviewers: X.C., Johns Hopkins School of Medicine; C.H., University of Cambridge; and C.I., Augusta University. Contributed by Maria I. New, September 2, 2020 (sent for review July 13, 2020; reviewed by Xu Cao, Christopher Huang, and Carlos Isales) Author contributions: S.H., H.X., M.I.N., C.J.R., A.J.H., T.Y., and M.Z. designed research; S.G., D.S., S.H., F.K., T.-C.K., M. Mathew, H.P.-P., H.X., H.C., K.M., Z.C., E.H., A.W., G.J., A.G., K.I., J.H., V.D., and D.L. performed research; S.G., D.S., S.H., T.-C.K., H.X., H.C., R.B., Z.C., E.H., C.R., A.M., S.M., H.M., P.S., V.R., V.D., M.A.Q., M. Meseck, S.-M.K., T.R.K., J.I., D.L., T.Y., and M.Z. analyzed data; and M.I.N., T.Y., and M.Z. wrote the paper. |
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| Snippet | Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH... We report the development and characterization of a first-in-class humanized antibody to follicle-stimulating hormone (FSH). We have shown previously that... |
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| SubjectTerms | Adipose Tissue - metabolism Animals Antibodies Antibodies, Blocking - chemistry Antibodies, Blocking - immunology Antibodies, Monoclonal Biological Sciences Biomedical materials Blocking Blocking antibodies Body fat Bone and Bones - metabolism Bone Density Bone mass Chemical compounds Cholesterol Epitopes Female Follicle Stimulating Hormone - chemistry Follicle Stimulating Hormone - immunology Follicle Stimulating Hormone, beta Subunit - immunology Follicle-stimulating hormone Humans Hypercholesterolemia Mice Mice, Inbred C57BL Molecular dynamics Molecular Dynamics Simulation Obesity Osteoporosis Peptide mapping Pharmacology Receptors Receptors, FSH - metabolism Structure-function relationships |
| Title | First-in-class humanized FSH blocking antibody targets bone and fat |
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