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Combining epitope-distinct antibodies to HER2: cooperative inhibitory effects on invasive growth

Oncogene volume 30, pages 1631–1642 (2011)Cite this article

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Abstract

Monoclonal antibodies (mAbs) to HER2 are currently used to treat breast cancer, but low clinical efficacy, along with primary and acquired resistance to therapy, commonly limit clinical applications. We previously reported that combinations of antibodies directed at non-overlapping epitopes of HER2 are endowed with enhanced antitumor effects, probably due to accelerated receptor degradation. Here, we extend these observations to three-dimensional mammary cell models, and compare the effects of single mAbs with the effects of antibody combinations. Collectively, our in vitro assays and computational image analyses indicate that combining mAbs against different epitopes of HER2 better inhibits invasive growth. Importantly, while growth factors are able to reduce intraluminal apoptosis and induce an invasive phenotype, combinations of mAbs better than single mAbs can reverse the growth factor-induced phenotypes of HER2-overexpressing spheroids. In conclusion, our studies propose that mAb combinations negate the biological effects of growth factors on invasive growth of HER2-overexpressing cells. Hence, combining mAbs offers a therapeutic strategy, potentially able to enhance clinical efficacy of existing antireceptor immunotherapeutics.

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Acknowledgements

We thank members of our group for insightful comments. AE is supported by a post-doctoral fellowship of the Minerva Foundation. YY is the incumbent of the Harold and Zelda Goldenberg Professorial Chair, and MS is the incumbent of the W Garfield Weston Professorial Chair in Immunolgy. Our work is supported by a collaborative program between Centre Leon-Berard, Canceropole Lyon Auvegne Rhône-Alpes and the Weizmann Institute, as well as by grants from the National Cancer Institute (CA072981), the European Commission, the German–Israeli Project Cooperation (DIP/DFG), the Israel Cancer Research Fund, the Dr Miriam and Sheldon G Adelson Medical Research Foundation, the Kekst Family Institute for Medical Genetics, the Kirk Center for Childhood Cancer and Immunological Disorders, the Women's Health Research Center funded by Bennett–Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the Estate of John M, Lang and the MD Moross Institute for Cancer Research.

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Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel

    A Emde, C-R Pradeep, D A Ferraro, N Ben-Chetrit & Y Yarden

  2. Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

    M Sela

  3. INRIA Rhône-Alpes, Project-team NUMED, Ecole Normale Supérieure de Lyon, Lyon, France

    B Ribba

  4. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel

    Z Kam

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  1. A Emde
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Correspondence to Y Yarden.

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Emde, A., Pradeep, CR., Ferraro, D. et al. Combining epitope-distinct antibodies to HER2: cooperative inhibitory effects on invasive growth. Oncogene 30, 1631–1642 (2011). https://doi.org/10.1038/onc.2010.547

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