Complement inhibitors are receiving significant interest currently towards inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, primarily in the form of monoclonal antibodies against the terminal products of complement activation most responsible for harmful inflammation. However, monoclonal antibody therapeutics are largely falling short of providing a broadly useful tool for inflammatory disease because they are rapidly cleared, have variable efficacy in broad patient populations, are expensive, and require regular infusions to maintain therapeutic concentrations. Cyclical dosing further induces the formation of anti-drug antibodies, and monoclonal antibody therapeutics miss the opportunity to controllably engage multiple complement components simultaneously to specifically reduce harmful inflammation. Owing to these challenges, complement inhibitors have only been approved for a limited number or complement-mediated disorders, and there remains a critical need for technologies that can selectively and stably neutralize multiple precisely targeted complement proteins for the treatment of chronic inflammatory conditions. This project focuses on the design of supramolecular (self-assembling) nanomaterials containing terminal complement proteins C3dg or C5a, which in previous work have been shown to raise therapeutic anti-inflammatory B-cell and T-cell responses in mice. In contrast to passive immunization with monoclonal antibodies, this active immunotherapy approach has advantageous durability and greatly simplified dosing requirements. The central objectives of the work are to design supramolecular complement assemblies towards two significant inflammatory diseases, rheumatoid arthritis and inflammatory bowel disease, and to clarify their protective mechanism of action. The work will be undertaken by a collaborative team with expertise in supramolecular materials, active immunotherapies, biomaterials for treating arthritis, and the pathophysiology of inflammatory bowel disease. The outcomes of this project are expected to be a demonstration that durable complement-neutralizing responses can be generated using supramolecular assemblies, and that these responses have therapeutic efficacy in mouse models of arthritis and inflammatory bowel disease. Broadly, these results will further champion the use of biomaterials-based strategies for active immunotherapy, thus providing an alternative to monoclonal antibodies and other protein biologics for treating not only inflammatory diseases, but a broad range of other targets in the future.

Current treatments for chronic inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease utilize manufactured antibodies to neutralize key inflammatory cytokines, but they possess limitations arising from the need for repeated injections, including sensitization to the biologic drug. In this project, we propose to develop active immunotherapies targeting terminal products of the complement system, which induce a patient to produce their own therapeutic immune responses, potentially solving this issue. This is achieved using innovative supramolecular assemblies of peptides and proteins, which are built in a modular fashion and facilitate the optimization of the strength and quality of the therapeutic antibody response.