Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16): Mechanistic Insights and New Therapeutic Opportunities

Interleukin-16 (IL-16) is reported to be a chemoattractant cytokine and modulator of T-cell activation, and has been identified as a ligand for CD4. The secreted active form of IL-16 has been detected at sites of TH1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI) and tissue transplant rejection. Neutralisation of IL-16 recruitment to CD4, using an anti-IL16 antibody, has been shown to significantly attenuate inflammation and disease pathology in IRI, as well as in some autoimmune diseases. The 14.1 antibody is a monoclonal anti-IL-16 antibody, which when incubated with CD4+ cells is reported to cause a reduction in the TH1-type inflammatory response. Secreted IL-16 contains a characteristic PDZ-domain. PDZ domains are typically characterised by a defined globular structure, along with a peptide-binding site located in a groove between the αB and βB structural elements and a highly conserved carboxylate-binding loop. The structure of the 14.1Fab fragment in complex with IL-16 has been solved by X-ray crystallography, revealing that binding of the antibody requires a conformational change in the IL-16 PDZ-domain. Our study reveals an unexpected mechanism of action for the mAb and identifies new opportunities for the further development of IL-16 targeted therapeutic drugs, including small molecules that mimic the interaction of the antibody.