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|Title:||Structure of a Potential Therapeutic Antibody Bound to Interleukin-16 (IL-16): Mechanistic Insights and New Therapeutic Opportunities|
Muskett, Frederick W.
Carr, Mark D.
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Citation:||Journal of Biological Chemistry, 2016, 291 (32), pp. 16840-16848|
|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.|
|Rights:||Copyright © 2016 American Society for Biochemistry and Molecular Biology. Deposited with reference to the publisher’s open access archiving policy.|
|Appears in Collections:||Published Articles, Dept. of Molecular and Cell Biology|
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|IL-16_JBC_2016.pdf||Post-review (final submitted author manuscript)||9.54 MB||Adobe PDF||View/Open|
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