SUN-196 Generation of Potent Inhibin Analogues

Despite the loss of ovarian inhibin’s at menopause being correlated with accelerated bone loss, and that exogenous inhibin’s can promote bone regeneration, the therapeutic utility of inhibins remains largely unexplored. Indeed, one of the major hurdles limiting inhibin (α/β dimers) exploration is an inability to produce these molecules free of contaminating activins (β/β dimers). Here, we describe an in vitro mutagenic approach to dramatically improve the purity and potency of inhibins. We identified key βA-subunit residues that, upon mutation, disrupted the formation of activin but had no affect on inhibin assembly. Once we could produce inhibin in the absence of activin, we sought to improve its potency via increased affinity for its receptors, ActRII and betaglycan. Targeted mutation of the predicted receptor binding faces on the inhibin α- and βA-subunits increased inhibin activity 30-fold. Significantly, we found that our inhibin agonists were bioactive in vivo, as measured by their ability to suppress circulating FSH following systemic administration in mice. Together these studies have characterised a means to generate pure inhibin agonists with markedly improved biological activity. Importantly, our inhibin agonists can only exert activity in target cells/tissues expressing inhibin’s co-receptor betaglycan, which should limit any off-target effects.