Chronic inflammatory diseases such as atherosclerosis, pulmonary inflammation, neuroinflammation, arthritis, and cancers collectively represent the leading cause of disease-related deaths and significant suffering worldwide. A key feature of these diseases is the uncontrolled migration of leukocytes to affected tissues. The migration of leukocytes in each inflammatory condition is promoted by specific groups of chemokines. Therefore, the selective inhibition of these chemokines presents a promising therapeutic approach.
Ticks have evolved the ability to naturally block chemokine-driven inflammation by secreting chemokine-binding proteins called "evasins" in their saliva. Natural evasins have shown efficacy in preclinical models of several inflammatory diseases. However, their therapeutic potential is limited by their broad specificity, which leads to the inhibition of off-target chemokines, and their short plasma half-life due to their small size (10-12 kDa). Thus, advancing evasins for clinical use requires engineering them to: (1) selectively target disease-associated chemokines while minimizing off-target interactions, and (2) extend their plasma half-life.
Our work has defined the structural basis of evasin-chemokine interactions and provided strategies for modifying evasins' chemokine selectivity. Recently, through structure-guided in vitro evolution (cell surface display of evasin mutant libraries, selection using desired chemokines, and characterisation with next-generation sequencing), we have engineered evasins to selectively inhibit chemokines associated with inflammatory diseases. Furthermore, to address the short half-life issue, we have produced fusion evasins by incorporating XTEN, a genetically encoded analogue of polyethylene glycol (PEG), and conducted pharmacokinetic analyses in mouse models.
Our findings have profound implications for developing a new generation of anti-inflammatory therapeutics. Specifically, our work presents a novel approach to modifying evasins for desired chemokine-binding profiles and enhanced pharmacokinetics, laying the foundation for future therapeutic applications.