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.