Rheumatoid Arthritis (RA) affects 1-2% of the world's population, including an estimated 2.5 million people in the US. Although therapies targeted at tumor necrosis factor alpha (TNF) have been highly successful, they are ineffective in up to 50% of individuals. RA remains a debilitating and life-long affliction for which there is a substantial unmet need for novel therapeutic approaches targeted at inhibiting mechanisms of inflammation other than TNF. Preliminary work in knock-out mice has shown that expression of factor B of the alternative complement pathway is essential for the development of severe arthritis induced by transfer of anti-type II collagen antibodies, and that inhibition of early complement pathways downregulates pro-inflammatory cytokine production. Taligen has licensed novel antibody inhibitors of factor B and is working towards developing these antibodies as a novel therapeutic for RA. This Phase I SBIR will accomplish the following: 1. Demonstrate that inhibition of factor B results in a 70% or greater reduction in clinical inflammation and joint injury when given either prior to or following the development of arthritis in the CIA model. 2. Identify the optimal monoclonal antibody candidate for further development in Phase II by determining the binding affinity and pharmacokinetics of inhibitory activity of each inhibitory antibody. After identifying the optimal mAb (longest half-life of inhibition in vivo), the effect of this mAb on the induction and the effector phases of arthritis will be examined in an active and a passive model of CIA. Criteria for success will be a 70% reduction in clinical and histologic scores and decreased C3 depostion and cytokine production in the synovium. Demonstration of a therapeutic effect of this magnitude will provide proof of principle for further development and the basis for a Phase II SBIR application focusing on affinity maturation (as necessary) of the optimal mAb candidate, antibody humanization and toxicology.
