Optimizing bone surface targeting of therapeutic antibodies for osteoporosis

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

PROJECT ABSTRACT Osteoporosis is the most common bone disease, affecting an estimated 10 million adults in the US alone and causing millions of fragility fractures each year. Existing therapies are plagued by low rates of treatment and poor adherence, largely due to concerns regarding infrequent but serious toxicities. Our way of improving the safety profile of osteoporosis therapies is to increase their local concentration by targeting them to bone. Our laboratories have recently developed technology which increases bone surface delivery of monoclonal antibodies (IgGs) by orders of magnitude and shown that this approach enhances the efficacy of a clinically relevant anti-sclerostin antibody (anti-Scl), while allowing lower dose and less frequent administration. The central hypothesis of the current proposal is that optimization of bone surface targeting parameters will enable local delivery of a wide range of therapeutic IgGs to both normal and osteoporotic bone, while ensuring target engagement and minimizing localization to areas of extraskeletal calcification. In Aim 1, we will optimize the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-Scl in both healthy mice and animals with an ovariectomy induced model of osteoporosis. We will then conduct a pre-clinical trial of the optimal form of targeted anti-Scl in animals with established osteoporosis, using a variety of translationally relevant endpoints. In Aim 2, we will optimize bone surface delivery of another IgG with clinical relevance in osteoporosis, anti-RANKL, which we hypothesize will require intermediate binding to the bone surface in order to allow optimal target engagement. Finally, in Aim 3, we determine if bone surface targeting of IgGs also induces accumulation in areas of extraskeletal calcification. We will vary bone surface targeting parameters and determine their impact on the localization of targeted anti-Scl, as well as its impact on the rate of vascular or valvular calcification. Key expected outcomes include optimized forms of anti-Scl and anti- RANKL which may be rapidly translated to large animal models and future clinical trials in osteoporosis.