The broad long term objective of the proposed research is to develop novel complement inhibitory proteins for the effective and safe treatment of autoimmune and inflammatory disease.
The specific aims of this application are to: 1. Prepare and characterize complement inhibitory proteins that can be targeted to specific tissues or sites of disease. Different classes of complement inhibitor will be fused to a targeting component consisting of either an antibody variable region or a receptor ligand. 2. Evaluate the therapeutic potential of targeted complement inhibitors in a murine model of spontaneous systemic lupus erythematosus (SLE). 3. Determine the effect of systemic complement inhibition on host ability to control an infection during chronic disease. Soluble CD59 or DAF functional units will be fused to either antibody fragments containing a variable region specific for a cell surface molecule, or to a soluble ligand recognizing selectins. Selectins are cell adhesion molecules that are expressed on inflamed endothelium and are involved in leukocyte recruitment. Various construct designs will be evaluated in vitro for selective targeting to a cell surface, and for their functional effectiveness at inhibiting complement and complement-dependent inflammatory processes. Complement inhibitory proteins based on antibody fusions that are effective in vitro will be tested in vivo in a murine model. A characterized murine anti-DNA antibody that has been shown to target to the kidney will be used for the preparation of IgG-complement inhibitor fusion proteins. Anti-DNA antibodies of the kind that will be used are relatively specific for lupus and have a pathogenic role in disease. Studies will determine the relative effects of targeted vs. untargeted (systemic) complement inhibitors, as well as the effect of selectively blocking the generation of different complement activation products. In addition to therapeutic evaluation, the proposed studies will allow testing of certain hypotheses relating to complement-associated disease mechanisms and the clinical use of complement inhibitors.
