The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20
Teeling, Jessica L., Mackus, Wendy J.M., Wiegman, Luus J.J.M., van den Brakel, Jeroen H.N., Beers, Stephen A., French, Ruth R., van Meerten, Tom, Ebeling, Saskia, Vink, Tom, Slootstra, Jerry W., Parren, Paul W.H.I., Glennie, Martin J. and van den Winkel, Jan G.J. (2006) The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. Journal of Immunology, 177, (1), 362-371.
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We have previously defined a panel of fully human CD20 mAb. Most of these were unexpectedly efficient in their ability to recruit C1q to the surface of CD20-positive cells and mediate tumor lysis via activation of the classical pathway of complement. This complement-dependent cytotoxicity (CDC) potency appeared to relate to the unusually slow off-rate of these human Abs. However, we now present epitope-mapping data, which indicates that all human mAb bind a novel region of CD20 that may influence CDC potency. Epitope mapping, using both mutagenesis studies and overlapping 15-mer peptides of the extracellular loops of CD20, defined the amino acids required for binding by an extensive panel of mouse and human mAb. Binding by rituximab and mouse CD20 mAb, had an absolute requirement for alanine and proline at positions 170 and 172, respectively, within the large extracellular loop of CD20. Surprisingly, however, all of the human CD20 mAb recognize a completely novel epitope located N-terminally of this motif, also including the small extracellular loop of CD20. Thus, although off-rate may influence biological activity of mAb, another critical factor for determining CDC potency by CD20 mAb appears to be the region of the target molecule they recognize. We conclude that recognition of the novel epitope cooperates with slow off-rate in determining the activity of CD20 Ab in activation of complement and induction of tumor cell lysis.
|Subjects:||Q Science > QR Microbiology > QR180 Immunology|
|Divisions:||University Structure - Pre August 2011 > School of Biological Sciences
|Date Deposited:||08 Aug 2008|
|Last Modified:||12 Jul 2013 01:05|
|RDF:||RDF+N-Triples, RDF+N3, RDF+XML, Browse.|
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