Abstract
Current treatments for chronic immune-mediated diseases such as psoriasis, rheumatoid arthritis, or Crohn's disease commonly rely on cytokine neutralization using monoclonal antibodies; however, such approaches have drawbacks. Frequent repeated dosing can lead to the formation of anti-drug antibodies and patient compliance issues, and it is difficult to identify a single antibody that is broadly efficacious across diverse patient populations. As an alternative to monoclonal antibody therapy, anti-cytokine immunization is a potential means for long-term therapeutic control of chronic inflammatory diseases. Here we report a supramolecular peptide-based approach for raising antibodies against IL-17 and demonstrate its efficacy in a murine model of psoriasis. B-cell epitopes from IL-17 were co-assembled with the universal T-cell epitope PADRE using the Q11 self-assembling peptide nanofiber system. These materials, with or without adjuvants, raised antibody responses against IL-17. Exploiting the modularity of the system, multifactorial experimental designs were used to select formulations maximizing titer and avidity. In a mouse model of psoriasis induced by imiquimod, unadjuvanted nanofibers had therapeutic efficacy, which could be enhanced with alum adjuvant but reversed with CpG adjuvant. Measurements of antibody subclass induced by adjuvanted and unadjuvanted formulations revealed strong correlations between therapeutic efficacy and titers of IgG1 (improved efficacy) or IgG2b (worsened efficacy). These findings have important implications for the development of anti-cytokine active immunotherapies and suggest that immune phenotype is an important metric for eliciting therapeutic anti-cytokine antibody responses.
Highlights
Anti-cytokine blockade with monoclonal antibodies has revolutionized the treatment of immune-mediated diseases by providing an efficacious treatment modality for multiple inflammatory conditions such as multiple sclerosis, rheumatoid arthritis, and plaque psoriasis [1]
Two potential B cell epitopes were selected: IL17.1 was selected from a previous report employing virus-like particles [28] and IL17.2 was selected from antigenicity prediction and its apparent availability on the protein surface (Figure 1A)
We show here that peptide self-assemblies displaying B-cell epitopes from IL-17A and exogenous T-cell epitopes can raise IL17A-specific antibodies and diminish symptoms of imiquimodinduced psoriasis in mice
Summary
Anti-cytokine blockade with monoclonal antibodies (mAbs) has revolutionized the treatment of immune-mediated diseases by providing an efficacious treatment modality for multiple inflammatory conditions such as multiple sclerosis, rheumatoid arthritis, and plaque psoriasis [1]. The effectiveness of mAbs can both be undercut by secondary resistance due to antidrug antibodies and difficulties developing mAb subclasses that are most therapeutically effective To counter these concerns, research has been undertaken to evaluate a new class of cytokine blockade therapies involving immunization against these inflammatory cytokines [5, 6]. Biomaterial platforms are being investigated for this purpose These therapies could provide an alternative to mAbs and could leverage the ability of biomaterials to induce tailored immune phenotypes in the context of long-term cytokine blockade therapy
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