Targeted Complement Inhibitors as Therapeutic Agents

DESCRIPTION (provided by applicant): Chronic Glomerulonephritis (chronic GN) is one of the most common forms of chronic renal disease, and is the third leading cause of renal failure in the US. While the classification of GN is complex and the etiology of many forms of chronic GN remains unknown, data suggest that antibody or immune complex-medicated deposition of complement plays a major role in many forms of this disease. Current therapies consist of nonspecific immunosuppression with cytotoxic agents or corticosteroids, with modest benefit and a significant risk for adverse events. However, the critical effector mechanism of renal damage in most forms of chronic GN is the complement system. Thus, inhibition of complement activation, preferably at the site of tissue injury, has the potential to specifically shut down the renal inflammatory response and thereby potentially augment or even replace current therapies. Recent studies performed in the laboratory of Taligen's collaborator Dr. Tomlinson have shown that targeting complement inhibitors to sites of complement activation and inflammation results in significant therapeutic benefit in terms of both efficacy and safety. The targeting strategy involves linking a complement inhibitory protein to a targeting moiety consisting of a fragment of complement receptor 2 (CR2). CR2 binds long-lived complement C3 fragments which have been deposited at sites of complement activation and thereby acts to target or "deliver" the attached complement inhibitor to the site of inflammation. Taligen Therapeutics has licensed the rights for CR2~complement inhibitor fusion proteins and their uses and has initiated a program to develop these molecules as therapeutic agents for chronic inflammatory diseases such as lupus nephritis. Blockade of complement activation early in the cascade at the level of C3 would be expected to have broad inhibitory effects as a result of inhibiting production of all downstream complement activation products. The aim of this Phase I SBIR proposal is to synthesize and compare the function of different human inhibitors of C3 to determine which of these inhibitors provides the most effective level of complement inhibition when linked to a CR2 targeting moiety.