Efficacy and safety of a therapeutic humanized FSH-blocking antibody in obesity and Alzheimer's disease models.

Abstract

There is growing evidence for direct actions of follicle-stimulating hormone (FSH) on tissues other than the ovaries and testes. Blocking FSH action, either genetically or pharmacologically, protects against bone loss, fat gain, and memory loss in mice. We thus developed a humanized FSH-blocking antibody--MS-Hu6--as a lead therapeutic for three diseases of public health magnitude--osteoporosis, obesity and Alzheimer's disease (AD) that track together in post-menopausal women. Here, we report the crystal structure of MS-Hu6 and its interaction with FSH in atomistic detail. Using our Good-Laboratory-Practice-Compliant platform (21CFR58), we formulated MS-Hu6 and the murine equivalent Hf2 at an ultra-high concentration; both formulated antibodies displayed enhanced thermal and colloidal stability. A single injection of 89Zr-labelled MS-Hu6 revealed a beta-phase t½ of 89 and 131 hours for female and male mice, respectively, with retention in regions of interest. Female mice injected subcutaneously with Hf2 displayed a dose-dependent reduction in body weight and body fat. Hf2 also rescued recognition memory and spatial learning loss in a context- and time-dependent manner in AD-prone 3xTg and APP/PS1 mice. MS-Hu6 injected into African green monkeys (8 mg/kg) intravenously, and then subcutaneously at monthly intervals, was safe, and without effects on vitals, blood chemistries or blood counts. There was a notable ~4% weight loss in all four monkeys after the first injection, which continued in two of four monkeys. We thus provide IND-enabling data towards an upcoming first-in-human study.