Modular complement assemblies for mitigating inflammatory conditions

Abstract

Significance Current treatments for chronic inflammatory conditions rely on biologic drugs, commonly monoclonal antibodies that interfere with inflammatory signaling pathways. These drugs have made enormous contributions to the treatment of inflammatory diseases but still possess considerable drawbacks, including high cost that limits access in low-resource settings, the requirement for regularly repeated injections, and uneven efficacy. As an alternative to such biologics, active immunotherapies, in which an individual is induced to generate their own therapeutic antibodies, offer considerable potential advantages. Here, we report chemically defined nanomaterials inducing therapeutic responses in two models of inflammation in mice. The materials were produced by coassembling defined T cell epitopes, B cell epitopes, and an engineered fragment of complement protein C3dg into defined nanomaterials. Complement protein C3dg, a key linkage between innate and adaptive immunity, is capable of stimulating both humoral and cell-mediated immune responses, leading to considerable interest in its use as a molecular adjuvant. However, the potential of C3dg as an adjuvant is limited without ways of controllably assembling multiple copies of it into vaccine platforms. Here, we report a strategy to assemble C3dg into supramolecular nanofibers with excellent compositional control, using β-tail fusion tags. These assemblies were investigated as therapeutic active immunotherapies, which may offer advantages over existing biologics, particularly toward chronic inflammatory diseases. Supramolecular assemblies based on the Q11 peptide system containing β-tail–tagged C3dg, B cell epitopes from TNF, and the universal T cell epitope PADRE raised strong antibody responses against both TNF and C3dg, and prophylactic immunization with these materials significantly improved protection in a lethal TNF-mediated inflammation model. Additionally, in a murine model of psoriasis induced by imiquimod, the C3dg-adjuvanted nanofiber vaccine performed as well as anti-TNF monoclonal antibodies. Nanofibers containing only β-tail–C3dg and lacking the TNF B cell epitope also showed improvements in both models, suggesting that supramolecular C3dg, by itself, played an important therapeutic role. We observed that immunization with β-tail–C3dg caused the expansion of an autoreactive C3dg-specific T cell population, which may act to dampen the immune response, preventing excessive inflammation. These findings indicate that molecular assemblies displaying C3dg warrant further development as active immunotherapies.