Targeted Lymphoma Cell Death by Novel Signal Transduction Modifications
نویسنده
چکیده
CD22 is a B-cell specific membrane glyco-protein that mediates homotypic and heterotypic celladhesion; it also regulates B-cell receptor (BCR)-mediatedsignals. Monoclonal antibodies (mAb) directed at theligand binding domain of CD22 initiate CD22-mediatedsignal transduction and apoptosis in B-cell lymphomas(NHL). Amino acid analysis of the complimentary deter-mining regions (CDRs) of six different anti-CD22 ligandblocking mAb revealed a high level of sequence conser-vation. The heavy chain CDRs 1, 2, and 3 are 85, 40, and38% conserved, respectively; light chain CDRs 1, 2, and 3,are 95, 90 and 90% conserved, respectively. Based on theseconserved sequences, five peptides were designed andsynthesized. Only the sequence derived from heavy chainCDR2 (Peptide 5) demonstrated significant B-cell binding.Peptide 5 bound to both malignant and primary B-cellswith very little T-cell binding. The affinity had a Km of5 9 10 M. Peptide 5 mediated killing of several NHLcell lines to a degree similar to that of the parent mAb(HB22.7). Peptide 5’s loop structure was shown to be crucial for B-cell binding and ligand blocking. Mutationalanalysis revealed that most Peptide 5 amino acids were critical for B cell binding. Using a CD22 transfected COScell line, we demonstrated CD22-specific binding andCD22 ligand blocking to a degree similar to HB22.7.Finally Peptide 5 was used as a vehicle to deliver a pro-apoptotic peptide into NHL cells. Peptide 5 was fused to aBH3 death domain-containing peptide which demonstratedmore effective NHL cell killing than the parent peptide.
منابع مشابه
XWH - 07 - 1 - 0471 TITLE : Targeted Lymphoma Cell Death by Novel Signal Transduction Modifications
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