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Affinity maturation of monoclonal antibody 1E11 by targeted randomization in CDR3 regions optimizes therapeutic antibody targeting of HER2-positive gastric cancer

Title
Affinity maturation of monoclonal antibody 1E11 by targeted randomization in CDR3 regions optimizes therapeutic antibody targeting of HER2-positive gastric cancer
Authors
KoB.-K.ChoiS.CuiL.G.LeeY.-H.HwangI.-S.KimK.-T.ShimH.J.-S.
Ewha Authors
심현보
SCOPUS Author ID
심현보scopus
Issue Date
2015
Journal Title
PLoS ONE
ISSN
1932-6203JCR Link
Citation
vol. 10, no. 7
Publisher
Public Library of Science
Indexed
SCIE; SCOPUS WOS scopus
Abstract
Anti-HER2 murine monoclonal antibody 1E11 has strong and synergistic anti-tumor activity in HER2-overexpressing gastric cancer cells when used in combination with trastuzumab. We presently optimized this antibody for human therapeutics. First, the complementarity determining regions (CDRs) of the murine antibody were grafted onto human germline immunoglobulin variable genes. No difference in affinity and biological activity was observed between chimeric 1E11 (ch1E11) and humanized 1E11 (hz1E11). Next, affinity maturation of hz1E11 was performed by the randomization of CDR-L3 and H3 residues followed by stringent biopanning selection. Milder selection pressure favored the selection of more diverse clones, whereas higher selection stringency resulted in the convergence of the panning output to a smaller number of clones with improved affinity. Clone 1A12 had four amino acid substitutions in CDR-L3, and showed a 10-fold increase in affinity compared to the parental clone and increased potency in an in vitro anti-proliferative activity assay with HER2-overepxressing gastric cancer cells. Clone 1A12 inhibited tumor growth of NCIN87 xenograft model with similar efficacy to trastuzumab alone, and the combination treatment of 1A12 and trastuzumab completely removed the established tumors. These results suggest that humanized and affinity matured monoclonal antibody 1A12 is a highly optimized molecule for future therapeutic development against HER2-positive tumors. Copyright: © 2015 Ko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI
10.1371/journal.pone.0134600
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일반대학원 > 바이오융합과학과 > Journal papers
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