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Potent synergistic anti-tumor activity of a novel humanized anti-HER2 antibody hersintuzumab in combination with trastuzumab in xenograft models

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Summary

Immunotherapy of HER2-overexpressing cancers by FDA approved monoclonal antibodies (mAbs) such as trastuzumab and pertuzumab has shown promising results. We have recently produced a novel humanized anti-HER2 mAb, hersintuzumab, which did not sterically inhibit binding of trastuzumab and pertuzumab to HER2, thus recognizing a distinct epitope on subdomain I + II of HER2. In this study, we assessed the in vitro and in vivo anti-tumor activity of this mAb individually and in combination with trastuzumab. Different HER2-overexpressing human cancer cell lines, including SKOV3, NCI-N87 HCC1954 and BT-474 were cultured and binding reactivity of Hersintuzumab to these cell lines was analyzed by flow cytometry. In addition, the inhibitory effect of different concentrations of hersintuzumab, trastuzumab and their combination on tumor cells growth was assessed by XTT assay. For Assessment of tumor growth inhibition in xenograft model, Balb/c athymic nude mice were subcutaneously injected with NCI-N87 and SKOV3 tumor cells and then treated intravenously with these mAbs. Our results showed that hersintuzumab could bind to all HER2-overexpressing cell lines similar to trastuzumab. In vitro experiments showed that both hersintuzumab and trastuzumab individually and in combination inhibited growth of all cell lines with the exception of HCC-1954.Inhibitory effect of the combination of mAbs was significantly higher than that of each mAb alone. Similar results were obtained in the gastric (NCI-N87) and ovarian (SKOV-3) tumor xenograft models. Hersintuzumab in combination with trastuzumab induces synergic anti-tumor effects on HER2-overexpressing cells in vitro and in vivo and is potentially a therapeutic tool for treatment of HER2-overexpressing cancers.

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Acknowledgements

This study was partially supported by grants from Tehran University of Medical Sciences (Grant No. 97-02-27-38550), Avicenna Research Institute (Grant No. 97-002) and National Animal Modeling Network and In vivo Research, Council for Development of Stem Cell Sciences and Technologies, Vice-Presidency for Science and Technology, grant number 98/11611.

Funding

The work was supported by grants from Tehran University of Medical Sciences (grant number 97–02–27-38550), Avicenna Research Institute (grant number 97–002) and National Animal Modeling Network and in vivo Research, Council for Development of Stem Cell Sciences and Technologies, Vice-Presidency for Science and Technology (grant number 98/11611).

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Authors and Affiliations

  1. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

    Fariba Shiravi, Mehdi Mohammadi, Forough Golsaz-Shirazi, Tannaz Bahadori, Mohammad Ali Judaki, Maryam Mobini, Mohammad Mehdi Amiri & Fazel Shokri

  2. Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

    Forough Fatemi, Hengameh Ahmadi Zare, Farzaneh Notash Haghighat & Mahmood Jeddi-Tehrani

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Contributions

FS and MMA made substantial contributions to the study conception, design, analysis and interpretation of the data. FS made substantial contributions to the design, acquisition, analysis and interpretation of the data. MM, FG-S, TB, MAJ, FF, HAZ, FNH, MM and MJ-T contributed to the acquisition of the data. The first draft of the manuscript was written by FS and MMA; FS commented on subsequent versions of the manuscript. All authors approved the final manuscript submitted to the journal.

Corresponding authors

Correspondence to Mohammad Mehdi Amiri or Fazel Shokri.

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Conflict of interest

Fariba Shiravi declares that she has no conflict of interest. Mehdi Mohammadi declares that he has no conflict of interest. Forough Golsaz-Shirazi declares that she has no conflict of interest. Tannaz Bahadori declares that she has no conflict of interest. Mohammad Ali Judaki declares that he has no conflict of interest. Forough Fatemi declares that she has no conflict of interest. Hengameh Ahmadi Zare declares that she has no conflict of interest. Farzaneh Notash Haghighat declares that she has no conflict of interest. Maryam Mobini declares that she has no conflict of interest. Mahmood Jeddi-Tehrani declares that he has no conflict of interest. Mohammad Mehdi Amiri declares that he has no conflict of interest. Fazel Shokri declares that he has no conflict of interest.

Ethics approval

This study was approved by the Ethical Committee of Tehran University of Medical Sciences. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Shiravi, F., Mohammadi, M., Golsaz-Shirazi, F. et al. Potent synergistic anti-tumor activity of a novel humanized anti-HER2 antibody hersintuzumab in combination with trastuzumab in xenograft models. Invest New Drugs 39, 697–704 (2021). https://doi.org/10.1007/s10637-020-01048-4

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