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Investigational New Drugs

, Volume 36, Issue 2, pp 171–186 | Cite as

Hersintuzumab: A novel humanized anti-HER2 monoclonal antibody induces potent tumor growth inhibition

  • Mohammad Mehdi Amiri
  • Forough Golsaz-Shirazi
  • Tahereh Soltantoyeh
  • Reza Hosseini-Ghatar
  • Tannaz Bahadori
  • Jalal Khoshnoodi
  • Shadi Sadat Navabi
  • Samira Farid
  • Mohammad Hossein Karimi-Jafari
  • Mahmood Jeddi-Tehrani
  • Fazel Shokri
PRECLINICAL STUDIES

Summary

Humanized monoclonal antibodies (mAbs) against HER2 including trastuzumab and pertuzumab are widely used to treat HER2 overexpressing metastatic breast cancers. These two mAbs recognize distinct epitopes on HER2 and their combination induces a more potent blockade of HER2 signaling than trastuzumab alone. Recently, we have reported characterization of a new chimeric mAb (c-1T0) which binds to an epitope different from that recognized by trastuzumab and significantly inhibits proliferation of HER2 overexpressing tumor cells. Here, we describe humanization of this mAb by grafting all six complementarity determining regions (CDRs) onto human variable germline genes. Humanized VH and VL sequences were synthesized and ligated to human γ1 and κ constant region genes using splice overlap extension (SOE) PCR. Subsequently, the humanized antibody designated hersintuzumab was expressed and characterized by ELISA, Western blot and flow cytometry. The purified humanized mAb binds to recombinant HER2 and HER2-overexpressing tumor cells with an affinity comparable with the chimeric and parental mouse mAbs. It recognizes an epitope distinct from those recognized by trastuzumab and pertuzumab. Binding of hersintuzumab to HER2 overexpressing tumor cells induces G1 cell cycle arrest, inhibition of ERK and AKT signaling pathways and growth inhibition. Moreover, hersintuzumab could induce antibody-dependent cell cytotoxicity (ADCC) on BT-474 cells. This new humanized mAb is a potentially valuable tool for single or combination breast cancer therapy.

Keywords

Antibody humanization Monoclonal antibody Breast cancer Immunotherapy HER2 

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Mohammad Mehdi Amiri
    • 1
  • Forough Golsaz-Shirazi
    • 1
  • Tahereh Soltantoyeh
    • 1
  • Reza Hosseini-Ghatar
    • 1
  • Tannaz Bahadori
    • 2
  • Jalal Khoshnoodi
    • 1
  • Shadi Sadat Navabi
    • 1
  • Samira Farid
    • 2
  • Mohammad Hossein Karimi-Jafari
    • 3
  • Mahmood Jeddi-Tehrani
    • 2
  • Fazel Shokri
    • 1
    • 2
  1. 1.Department of Immunology, School of Public HealthTehran University of Medical SciencesTehranIran
  2. 2.Monoclonal Antibody Research CenterAvicenna Research Institute, ACECRTehranIran
  3. 3.Department of Bioinformatics, Institute of Biochemistry and BiophysicsUniversity of TehranTehranIran

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