Immunomodulatory Biomaterials via Peptide and Protein Self-Assembly

点击翻译按钮获取中文摘要

Chronic inflammatory conditions such as rheumatoid arthritis, psoriasis, and Crohn’s disease are currently treated using biologics such as monoclonal antibodies and other protein inhibitors of inflammatory cytokines. These passive immunotherapies, where exogenously produced antibodies are repeatedly injected to neutralize a target of interest, have seen considerable success in recent years not only towards inflammatory conditions but across a broad range of diseases including cancer, diabetes, cardiovascular disease, and others. However, passive immunotherapies possess many shortcomings, including the need for frequent and repeated injections of manufactured proteins, close patient monitoring, high production costs, and a risk of sensitization that is heightened by repetitive administration. As a solution, active immunotherapies that elicit the production of therapeutic antibody responses by the patient represent an attractive alternative. However, the development of anti-cytokine active immunotherapies is challenged by a lack of available immunotherapy platforms capable of raising the narrowly defined immune responses necessary and avoiding autoreactivity. In this project we will address this challenge by designing supramolecular peptide materials capable of eliciting epitope-specific B cell/antibody responses against three key inflammatory cytokines pivotally involved in the pathogenesis of chronic inflammatory diseases. The work is enabled by previous funding of this project, in which self-adjuvanting, non-inflammatory, modular supramolecular peptide nanofibers have been developed. In Aim 1, peptide assemblies will be designed that raise antibody responses but negligible T-cell responses against the inflammatory cytokines TNF, IL-1b, and IL-17. In Aim 2, strategies for modulating the strength, phenotype, affinity, and persistence of anti-cytokine immune responses will be developed, and the biodistribution and clearance of the nanomaterials will be investigated. In Aim 3, single- and multi-epitope active immunotherapies will be developed for treating rheumatoid arthritis in a mouse model, and preclinical safety will be assessed. The expected outcomes are 1) a proof-of-concept that durable, therapeutic antibody responses can be generated in mice against several key inflammatory cytokines, 2) optimized formulations of multiple co- assembled peptides that raise maximally therapeutic antibody responses, and 3) articulated design rules for controlling the strength, affinity, duration, and immune phenotype of the immune responses raised. The work will be conducted by a research team with broad expertise in biomaterials, immunology, and inflammatory processes.