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

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 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.

A Single Multipurpose FSH–Blocking Therapeutic for Osteoporosis and Obesity

“…Because MS-Hu6 is not fully "human", we first determined its "humanness" in silico by inputting the VL and VH sequences into abYsis. Comparison of Z-scores revealed a rightshift in comparison with the human-mouse chimeric antibody (26), and in correspondence with human IgG1 (Fig. 6C).…”

“…for 8 weeks. The latter dose was based on the in vitro IC50 of MS-Hu6, which was ~30-fold lower than our polyclonal Ab (26). We determined net food intake and measured body weight weekly, and performed quantitative nuclear magnetic resonance (qNMR) at 8 weeks.…”

“…For predicting the pI value MS-Hu6, we inputted its sequence into Expasy (Swiss Bioinformatics Research Portal, https://web.expasy.org/compute_pi/). For predicting the "humanness" of humanized MS-Hu6 versus parent chimera and other humanized or fully human molecules (26)…”

“…We fine mapped the three top candidates to document subtle differences in binding modes (26). In addition, we established that MS-Hu6 blocked the binding of labeled recombinant human FSH to the FSHR, and in doing so, inhibited osteoclastogenesis and promoted beiging of adipocytes in vitro (26). Here, we studied the effect of MS-Hu6 on body composition in male ThermoMice fed ad libitum on a high fat diet.…”

Recent advances in understanding gonadotropin signaling

“…These accumulating experimental data seem to clearly debunk the classic view of gonadotropin physiology, potentially leading to new diagnostic, therapeutic, and prognostic opportunities. For instance, the use of anti-FSH antibodies for bone- and fat-specific targeting was proposed for clinical testing 267 . However, the issue is highly debated, and several objections, including the low reliability of the antibodies used for investigating FSHRs in non-canonical tissues 268 , firmly oppose the existence of extragonadal FSHRs and LHCGRs 269 .…”