CD6 monoclonal antibodies differ in epitope, kinetics and mechanism of action

Immunology
Lee I GarnerM H Brown

Abstract

CD6 is a type I T-cell surface receptor that 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 characterized 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 interleukin-2 production by a cell line expressing a chimeric antigen receptor containing the extracellular region ...Continue Reading

References

Dec 8, 1998·The Journal of Experimental Medicine·M H BrownA N Barclay
Mar 30, 2004·European Journal of Immunology·Namir J HassanMarion H Brown
Aug 6, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Idoia GimferrerFrancisco Lozano
Feb 8, 2005·Nature Immunology·Edward J EvansSimon J Davis
Aug 18, 2006·Molecular and Cellular Biology·Namir J HassanMarion H Brown
Sep 27, 2006·Acta Crystallographica. Section D, Biological Crystallography·A Radu AricescuE Yvonne Jones
Mar 21, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Mónica A A CastroAlexandre M Carmo
Aug 19, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·David M KoflerDavid A Hafler
Oct 1, 2011·European Journal of Immunology·Marta I OliveiraAlexandre M Carmo
Oct 11, 2012·Immunological Reviews·Omer DushekP Anton van der Merwe
Dec 10, 2013·Nature Biotechnology·Killugudi Jayaraman
May 7, 2015·Clinical, Cosmetic and Investigational Dermatology·Roshni Menon, Brinda G David
Jul 7, 2015·Structure·Paul E ChappellMarion H Brown
Jul 6, 2016·The Journal of Experimental Medicine·Marc Orta-MascaróFrancisco Lozano
Feb 18, 2017·Proceedings of the National Academy of Sciences of the United States of America·Yan LiFeng Lin
Mar 16, 2017·Molecular and Cellular Biology·Johannes Breuning, Marion H Brown
Feb 24, 2018·Journal of Autoimmunity·Lingjun ZhangFeng Lin

❮ Previous
Next ❯

Citations

Jan 9, 2019·Frontiers in Immunology·Carine M GonçalvesAlexandre M Carmo
Jan 12, 2020·Immunology

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

Antibody Specificity

Antibodies produced by B cells are highly specific for antigen as a result of random gene recombination and somatic hypermutation and affinity maturation. As the main effector of the humoral immune system, antibodies can neutralize foreign cells. Find the latest research on antibody specificity here.

Related Papers

The Journal of Immunology : Official Journal of the American Association of Immunologists
M H Brown, Erica Lacey
Acta Crystallographica. Section F, Structural Biology Communications
Alexey TeplyakovGary L Gilliland
© 2022 Meta ULC. All rights reserved