Biomaterial immunomodulators engaging natural antibody responses

About This Grant

Inflammatory diseases are currently treated using biologics that block single inflammatory mediators such as specific cytokines, and while these therapies have significantly advanced the treatment of many diseases including inflammatory bowel disease, rheumatoid arthritis, psoriasis, and others, they still possess numerous serious shortcomings. Cytokine-blocking biologics only neutralize one target in a complex network of signalling molecules, so they suffer from highly variable efficacy, and they cease working for large percentages of patients. They also must be dosed repeatedly, which can induce the development of anti-drug antibodies that result in treatment failure. These shortcomings of current treatments mean that patients experience significant unpredictability in the management of their disease, frequent treatment changes, extensive monitoring, and a high volume of provider visits as treatments are continuously assessed and updated, leading not only to significant morbidity but considerable burden on the US healthcare system. For these reasons, there is a critical unmet need for entirely new treatment approaches that can safely and stably provide long-lasting immunomodulation for the treatment of chronic inflammatory conditions. This project focuses on designing a new broadly applicable therapeutic approach to treat chronic inflammatory diseases using supramolecular (self-assembling) biomaterials to engage multifactorial repair pathways central to chronic and acute inflammation. The technology, termed Immunomodulatory Self-Assembled Peptides (ISAP) engages a critical aspect of the immune system known as natural autoantibodies (NAAbs), which have been identified as protective factors for multiple chronic inflammatory diseases including inflammatory bowel disease, inflammatory lung disease, atherosclerosis, lupus, chronic kidney disease, and others. The central objectives of the proposed research are to optimize ISAP to treat inflammation of the colon and lung and to develop design rules for maximizing its therapeutic efficacy. The work will be conducted by a collaborative team of engineers and physicians with expertise in biomaterials, colitis, and inflammatory lung diseases. The outcomes of this project are expected to be a demonstration that durable NAAb-engaging responses can be generated using ISAP, and that these responses have therapeutic efficacy in mouse models of colitis and inflammatory lung disease. The project will also lay the groundwork for the future exploration of biomaterials, and molecular assemblies in particular, as broadly applicable immunomodulatory platforms for treating a wide range of inflammatory diseases and conditions.