AI-validated fusion proteins for local inhibition of interleukin-17A.

IL-17A is a potent immunomodulatory cytokine that is upregulated in many disorders characterized by chronic inflammation, including autoimmune-mediated dry eye observed in patients with Sjögren's Disease. Existing IL-17A inhibiting therapies are delivered systemically and have been associated with increased infection rates in patients. Inhibiting IL-17A signaling locally, only in affected tissues, may provide therapeutic benefits without compromising systemic immune functions. To address this unmet need, we have developed a local IL-17A inhibiting therapy by fusing HAP, a peptide which binds and inhibits IL-17A, with elastin-like polypeptides (ELPs), which are intrinsically disordered thermosensitive protein-polymers that can be engineered to undergo liquid-liquid phase separation to form depots after injection. We show tuning of ELP composition allows us to manipulate the pharmacokinetics, and specifically mean absorption time of our local immunosuppressive depots, demonstrating the potential for extended, local therapy. Furthermore, the fusions retain the binding and inhibitory activity of the HAP peptide, aligning with our in silico predictions using AlphaFold3. Finally, we confirmed that our formulations, which are bacterially derived, do not measurably stimulate the innate or adaptive immune system, which is critical for therapies for autoimmune diseases. Together, these findings establish the utility of our novel peptide-ELP fusions for extended local IL-17A inhibition to address chronic inflammation with fewer off-target effects.