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Affinity Improvement and Humanization of Anti-Her2 Antibody A21 Based on Computational Simulation

Author: ChangLiang
Tutor: LiuJing
School: University of Science and Technology of China
Course: Cellular and Molecular Immunology
Keywords: Anti- Her2 antibody Docking Computational Design Affinity transformation CDR-grafted Human Transformation
CLC: R392
Type: PhD thesis
Year: 2010
Downloads: 98
Quote: 0
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Abstract


Chimeric antibody chA21 is constructed in our laboratory engineering of an anti p185/Her2 person - mouse chimeric antibody against p185/Her2 high expression of the tumor has obvious inhibitory activity. And other strains have been used in clinical drug Herceptin antibody anti p185/Her2 comparison , chA21 antigen antibody affinity and immunogenicity some deficiencies. In order to make it more suitable for tumor therapy , we based on protein structure simulation conducted chA21 affinity for renovation and transformation of human origin . We calculate the design point mutation on A21 affinity has been transformed. First, we scanned through point mutations , precise identification of the A21 antigen epitopes , and established a new antibody complementarity determining region (CDR) of the classification method , using this new method for each antibody A21 CDR region involved in antigen recognition loci were predicted. Based on the results of these analyzes , through computer simulation of molecular docking , more finely A21 and Her2 reveals interaction mode and predicted by calculation , designed to transform an antigen affinity antibodies A21 mutation scheme and a preliminary experiments . In addition , we combine molecular docking simulation and measurement results of the previous activity , from a structural perspective of the A2l epitope recognition mechanism for its tumor suppressor correlation . To reduce the immunogenicity of chimeric antibody chA21 , CDR-grafting method we its murine variable region of humanized transformation . A21 based on the variable region sequence and structure information and select a humanized antibody as a humanized huCC49 template transplantation antigen- binding region , based on the humanized antibody after transplantation analog architecture , a number of important framework region residues for mutation direction screening , choose a more stable structure in accordance with antibodies to mutations direction obtained A2l a humanized variants H1, ??H1-1, H1-2 sequences. In eukaryotic expression system 293T Fc fusion of a humanized variant of expression , affinity analysis showed that compared with the chimeric antibody A21 , A21 design humanized antibodies H1, ??H1-1, H1-2 and antigen similar affinity , and has reached a fully humanized , has better prospects for clinical application .

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CLC: > Medicine, health > Basic Medical > Medical Immunology
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