Complement Inhibitors as DMOADs

DESCRIPTION (provided by applicant): Complement system play a role in preventing inflammation and joint immobility. Osteoarthritis (OA), an inflammatory disease of the joints, is quite prevalent among the elderly and causes disability in nearly 10% of thepopulation over 55 years. Current medications only manage the disease and do not cure or halt the disease. The prevalence of OA coupled with the absence of Disease Modifying Osteoarthritis Drugs (DMOADs) heightens the negative impact of this disease on humanity. Recent studies have shown that cytokines are important in the development and progression of OA. It has been hypothesized that neutralizing IL-12 or TNF-1 may provide benefit to OA patients, hence, biologics or drugs that neutralize these cytokines are being investigated. Clinical trials with an anti-TNF-1 antibody are currently ongoing. The alternative pathway (AP) of complement has recently been implicated in the etiology of OA. We have developed a proprietary group of antibodies that selectivelytarget the AP without affecting the host defense mediated via the classical pathway (CP). Our preliminary results suggest that the AP plays an important role in the development and progression of OA and that our target antibody is highly effective in resolving OA as indicated by rabbit models of OA. The current application proposes development of a humanized IgG1 as a potent treatment for halting and arresting the progression of OA in humans. In the Phase I segment, we further test a specific neutralizinganti-complement monoclonal antibody in the young rabbit OA model. In the Phase II segment, we will study the efficacy of the targeted humanized antibody to aged rabbits, evaluate the efficacy of the biologic in multiple modes of administration, and establish protocol for scaled up preparation of the humanized antibody. Our studies will provide new insight into the development of novel therapies for the treatment of OA. Overall, the proposed work is a critical step in the direction of developing a cost-effective, efficacious and safe therapeutic agent for preventing joint damage caused by OA. PUBLIC HEALTH RELEVANCE Osteoarthritis (OA) is a disease which targets the elderly population, and affects a large number of people worldwide. Despite tremendous efforts, no effective and safe treatment is currently available. The treatment of OA is focused on managing pain and swelling, improving quality of life, and minimizing disability. There are no disease-modifying drugs (DMOADs) available at this time, sothe disease management is primarily with acetaminophen, non-steroidal antiinflammatory drugs (ibuprofen, naproxen, indomethacin, etc), cyclooxygenase-2 selective inhibitors (celecoxib, etoricoxib, etc), and other non-opiate and opiate analgesics. Intra-articular corticosteroid injections provide benefit in some patients. NovelMed intends to develop a Disease Modifying Treatment for Osteoarthritis. We have developed a humanized monoclonal antibody that displays exciting results in resolving OA in the rabbitmodel. This application proposes to further evaluate the use of this antibody in juvenile and aged rabbits.