Journal of Computer-Aided Molecular Design

, Volume 24, Issue 1, pp 37–47 | Cite as

Interactions between anti-ErbB2 antibody A21 and the ErbB2 extracellular domain provide a basis for improving A21 affinity

  • Liang Chang
  • Changhai Zhou
  • Man Xu
  • Jing Liu


Anti-ErbB2 antibodies are well researched for the therapy of ErbB2-overexpressing tumors. The therapeutic potential and efficacy of these antibodies are closely related to their affinities to ErbB2. Previously we reported that an anti-ErbB2 antibody A21 targeting a conformational epitope comprising several loops in ErbB2 extracellular subdomain I and II could inhibit the proliferation of ErbB2-overexpressing cancer cells in vitro and in vivo. Here we found that another structureless and non-conserved loop in subdomain I of ErbB2 extracellular domain (ECD) was important for binding to A21, and then the antigen-contact sites on A21 were determined by site-directed mutation. The loop was constructed by molecular modeling, and a new model of A21-ErbB2 complex was generated by docking using the crystal structure of the scfv A21 and the model of ErbB2 ECD with the loop built. Based on the complex model, computational design for A21 affinity improvement was performed to enhance its affinity to ErbB2. Two mutants with about 1.7-fold improvement in affinity were obtained. Our study provided a rational molecular basis for affinity improvement and mechanism investigation of A21.


ErbB2 Epitope loop Internalizing antibody Docking Inhibitory mechanism 



We thank Thomas P. Garrett and Colin W. Ward for helpful discussions and the gift of the atomic coordinates of EGFR dimer. This work is supported by Hi-Tech Research and Development Program (“863” Program) of the Ministry of Science and Technology of China (no. 2006AA02A245), Specialized Research Fund for the Doctoral Program of Higher Education (no. 20060358021) and National Natural Science Fund of China (no. 30570362).


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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Lab of Cellular and Molecular Immunology, School of Life SciencesUniversity of Science and Technology of ChinaHefeiPeople’s Republic of China
  2. 2.Hefei National Laboratory for Physical Sciences at the Microscale, School of Life SciencesUniversity of Science and Technology of ChinaHefeiPeople’s Republic of China

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