First-in-class humanized FSH blocking antibody targets bone and fat

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 46; pp. 28971 - 28979
• Main Authors: Gera, Sakshi, Sant, Damini, Haider, Shozeb, Korkmaz, Funda, Kuo, Tan-Chun, Mathew, Mehr, Perez-Pena, Helena, Xie, Honglin, Chend, Hao, Batista, Rogerio, Ma, Kejun, Cheng, Zhen, Hadelia, Elina, Robinson, Cemre, Macdonald, Anne, Miyashita, Sari, Williams, Anthony, Jebian, Gregory, Miyashita, Hirotaka, Gumerova, Anisa, Ievleva, Kseniia, Smith, Pinar, He, Jiahuan, Ryu, Vitaly, DeMambro, Victoria, Quinn, Matthew A., Meseck, Marcia, Kim, Se-Min, Kumar, T. Rajendra, Iqbal, Jameel, New, Maria I., Lizneva, Daria, Rosen, Clifford J., Hsueh, Aaron J., Yuen, Tony, Zaidi, Mone
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.11.2020
• Subjects: 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; adipose; follicle-stimulating hormone; monoclonal antibody; humanization
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2014588117

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.