A Humanized Monoclonal FSH Blocking Antibody for Alzheimer's Disease - PROJECT SUMMARY Thanks to the ongoing parent U01 AG073148, we are currently moving our humanized follicle–stimulating hormone– (FSH–) blocking antibody, Hu6, through early phase development for future use not only in Alzheimer’s disease (AD), but also in osteoporosis, obesity, and dyslipidemia. The premise underscoring the use of Hu6 in four diseases of public health magnitude, importantly AD, for which the therapeutic armamentarium is severely limited, rests on observations that FSH directly causes bone loss, adiposity, hypercholesterolemia, and neurodegeneration in mouse models, and that blocking FSH action, genetically or pharmacologically, prevents these adverse effects. Towards the objective of moving Hu6 into people, we have achieved multiple milestones per our U01 AG073148. First, we have solved the crystal structure of Hu6, and are now attempting to solve the structure of the Hu6:FSH complex. Second, we have created a Good Laboratory Practice (GLP) platform in accordance with 21 CFR Part 58, which will allow data to be part of our dossier for an Investigational New Drug (IND) application to the Food and Drug Administration (FDA). The GLP platform also requires extreme transparency and enables rigor. Third, using this platform, we have generated a formulation for Hu6 for it to be dosed in human as a therapeutic. Physicochemical testing shows that formulated Hu6 displays monomeric, colloidal, structural, thermal, and accelerated stability. Fourth, we have generated three CHOK1–based stable cell lines that express adequate levels of Hu6—one of these is being utilized to generate a master cell bank in our current Good Manufacturing Practice (cGMP) facility. Fifth, we have studied the biodistribution and pharmacokinetics of Hu6 in several mouse models and in monkeys. Sixth, efficacy studies have revealed positive effects of Hu6 in preventing memory loss in a context– and time–dependent manner in mouse models of AD, namely 3xTg and APP/PS1 mice. Lastly, using African Green monkeys, we document that Hu6 does not alter vital signs, blood counts or blood chemistries. As we prepare for an IND filing for a phase 1b/2a clinical study, we are at a critical point in terms of (a) manufacturing clinical grade Hu6 and (b) formal toxicology studies; we have internal funding for the latter. The goal for this Revision is therefore to generate sufficient quantities of clinical grade Hu6 for first–in–human studies. Thus, our Specific Aim is to work with a Contract Development and Manufacturing Organization (CDMO), likely GBI (Plantation, FL), on a fee–basis to manufacture therapeutic Hu6. The manufacturing involves multiple highly regulated steps to develop, optimize, verify, and replicate both upstream and downstream processes prior to a final GMP run in a 200L bioreactor. With the clinical grade Hu6 and additional data on toxicology, we will submit an IND application to the FDA for the human trial of Hu6 for Alzheimer’s disease.
