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Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16)

DOI: 10.1074/jbc.M115.709303 DOI Help

Authors: Gareth Hall (University of Leicester) , Eilish Cullen (MRC Technology) , Kovilen Sawmynaden (MRC Technology) , Joanne Arnold (MRC Technology) , Simon Fox (MRC Technology) , Richard Cowan (University of Leicester) , Frederick W. Muskett (University of Leicester) , David Matthews (MRC Technology) , Andrew Merritt (MRC Technology) , Catherine Kettleborough (MRC Technology) , William Cruikshank (Boston University School of Medicine) , Debra Taylor (MRC Technology) , Richard Bayliss (University of Leicester) , Mark D. Carr (University of Leicester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 291 , PAGES 16840 - 16848

State: Published (Approved)
Published: August 2016

Abstract: 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.

Journal Keywords: cytokine; interleukin; monoclonal antibody; nuclear magnetic resonance (NMR); protein crystallization; interleukin-16

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography