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CD6 mAbs differ in epitope, kinetics and mechanism of action.

08:00 EDT 17th May 2018 | BioPortfolio

Summary of "CD6 mAbs differ in epitope, kinetics and mechanism of action."

CD6 is a type I T cell surface receptor which modulates antigen receptor signalling. Its activity is regulated by binding of its membrane proximal domain (domain 3) to a cell surface ligand, CD166. CD6 monoclonal antibodies (mAbs) specific for the membrane distal domain (domain 1) perturb CD6 function including itolizumab (Alzumab ) which has reached the clinic for treatment of autoimmune disease. We characterised molecular and functional properties of several CD6 mAbs including itolizumab to define potential mechanisms of action. Epitope mapping using the crystal structure of CD6 to design mutants identified two distinct binding sites on different faces of domain 1, one containing residue R77, crucial for MT605 and T12.1 binding and the other, E63 which is crucial for itolizumab and MEM98. Analysis of binding kinetics revealed that itolizumab has a lower affinity compared with other CD6 domain 1 mAbs. We compared potential agonistic (triggering) and antagonistic (blocking) properties of CD6 mAbs in assays where the mechanism of action was well defined. CD6 domain 1 and 3 mAbs were equally effective in triggering IL-2 production by a cell line expressing a chimeric antigen receptor containing the extracellular region of CD6. CD6 domain 1 mAbs hindered binding of multivalent immobilised CD166 but were inferior compared with blocking by soluble CD166 or a CD6 domain 3 mAb. Characterisation of CD6 mAbs provides an insight into how their functional effects in vivo may be interpreted and their therapeutic use optimised. This article is protected by copyright. All rights reserved.

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This article was published in the following journal.

Name: Immunology
ISSN: 1365-2567
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