Mount Sinai Center for Translational Medicine and Pharmacology

Can we block FSH action toward a therapeutic benefit for osteoporosis, obesity, and Alzheimer’s disease simultaneously, particularly in women undergoing menopause? To test this possibility, we developed several antibodies that bind to a 13-amino-acid-long epitope of the active subunit of FSH. By doing so, we hoped to prevent its interaction with the FSH receptor. We found that our polyclonal FSH-blocking antibody and two murine monoclonal antibodies, Mf4 and Hf2, raised to the mouse and human epitopes, respectively, reduced bone loss. These antibodies differed in just two non-interacting amino acids. In separate studies, we found that the antibodies prevented fat gain in addition to causing beiging of white adipose tissue and inducing energy expenditure. These data phenocopied genetic FSH receptor haploinsufficiency, wherein mice display high bone mass and reduced fat mass. It was also consistent with an interventional study in patients with prostate cancer, in which orchiectomized males display higher body weight and fat mass compared with men receiving the GnRH agonist triptorelin––in essence, establishing that the reduction of serum FSH, even in males, can result in less weight gain. In separate studies, we found that FSH-blocking antibody also attenuated the onset of spatial memory defect and neuropathology in Alzheimer’s-prone 3xTg mice.

We have humanized Hf2 to yield 30 clones, from which we selected MS-Hu6 as the lead therapeutic.  This selection was achieved through in silico molecular dynamics to estimate the global net electrostatic energy (ΔΔG), and experimentally, using surface plasmon resonance. MS-Hu6 had the most negative ΔΔG and displayed a K_D of 7.52 nM, akin to that of trastuzumab, an antibody commonly used to treat breast cancer. MS-Hu6 bound to and prevented the binding of FSH to its receptor, and as expected, inhibited both osteoclast formation and adipogenic gene expression in vitro. In parallel, in vivo studies contemporaneously replicated in two labs showed increases in bone formation and bone mass in both wild type (Zaidi Lab) and ovariectomized mice (Rosen Lab at Maine Health Institute for Research). We also examined the pharmacokinetics and biodistribution of intravenous and intraperitoneal MS-Hu6 in three mouse models, namely C57BL/6, CD1, and Tg32 mice. Finally, and importantly, in collaboration with the Biopharmaceutical and Nanomedicine Development CoRE, we created an ultra-high concentration (100 mg/mL) antibody formation that displays thermal, colloidal, structural, stress, and accelerated stability. 

We propose to move MS-Hu6 into the first-in-human studies using the subcutaneous route, toward which we have developed a Good Laboratory Practice (GLP) platform within the Biopharmaceutical and Nanomedicine Development CoRE. We now have preclinical data of key aspects of MS-Hu6 that facilitate Investigational New Drug (IND) filings. First, we solved the crystal structure of MS-Hu6. Second, we undertook a detailed assessment of the pharmacokinetics and biodistribution of MS-Hu6, administered subcutaneously. Third, we performed a comprehensive safety study in monkeys. Fourth, we showed that FSH-blockade by Hf2, the parent monoclonal antibody, dose dependently prevented body weight and fat gain in a mouse model of diet-induced obesity. Finally, and importantly, we showed that Hf2 prevented the onset of cognitive decline in Alzheimer’s-prone 3xTg and APP/PS1 mice. The studies together not only position us favorably to move MS-Hu6 into humans, but also provide a compelling rationale for conducting high-quality, IND-enabling studies in academic medical centers.