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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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Methods used for studying the interactions of antibodies with specific regions of protein antigens. Important applications of epitope mapping are found within the area of immunochemistry.
Agents that aid or increase the action of the principle drug (DRUG SYNERGISM) or that affect the absorption, mechanism of action, metabolism, or excretion of the primary drug (PHARMACOKINETICS) in such a way as to enhance its effects.
Coronary vasodilator with a novel mechanism of action; proposed as antianginal agent.
An antidepressive agent that has also been used in the treatment of movement disorders. The mechanism of action is not well understood.
An anticonvulsant that is used in a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.
An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples of antigens include microorganisms (such as bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produc...
Monoclonal antibodies MAbs
Monoclonal antibodies recognise and attach to specific proteins produced by cells. Types of monoclonal antibodies used to treat cancer cells: Block cell dividing dividing signals Transport cancer drugs or radiation to cancer cells Tr...