Cancer Immunology, Immunotherapy

, Volume 61, Issue 7, pp 991–1003 | Cite as

Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells

  • Tracy R. Daniels
  • Richard K. Leuchter
  • Rafaela Quintero
  • Gustavo Helguera
  • José A. Rodríguez
  • Otoniel Martínez-Maza
  • Birgit C. Schultes
  • Christopher F. Nicodemus
  • Manuel L. Penichet
Original Article

Abstract

Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FcεRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECDHER2) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FcεRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECDHER2. Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FcεRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers.

Keywords

HER2/neu IgE Immunotherapy Cancer AllergoOncology 

Notes

Acknowledgments

We thank Lin Wang, Julie Lucas, and Sara Buczynski (AIT, Inc.) for their assistance with this project. We also thank Dr. Andrew Saxon, Dr. Ke Zhang, Dr. Sherie L. Morrison, Ryan K.Trinh, and Letitia A. Wims (UCLA) for their support to this project and Dr. Gang Li and Xuyang Lu (UCLA) for statistical consultation. This work was funded in part by NIH/NCI R41CA137881, R01CA136841, R01CA121195, K01CA138559, R01CA57152, ANPCyT-FONARSEC PICT-PRH 2008-00315, the Susan G. Komen Breast Cancer Foundation Basic, Clinical and Translational Research Grant BCTR0706771, and by Advanced Immune Therapeutics, Inc. The UCLA Jonsson Comprehensive Cancer Center and Center for AIDS Research Flow Cytometry Core Facility is supported by the NIH Awards CA16042 and AI28697, the Jonsson Cancer Center, the UCLA AIDS Institute, and the UCLA School of Medicine. Gustavo Helguera is member of the National Council for Scientific and Technological Research (CONICET), Argentina.

Conflict of interest

CFN and BCS are advisors to and own shares in Advanced Immune Therapeutics, Inc. All other authors have no conflicts to disclose.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Tracy R. Daniels
    • 1
  • Richard K. Leuchter
    • 1
  • Rafaela Quintero
    • 1
  • Gustavo Helguera
    • 1
    • 7
  • José A. Rodríguez
    • 1
    • 4
  • Otoniel Martínez-Maza
    • 2
    • 3
    • 5
    • 6
  • Birgit C. Schultes
    • 8
    • 9
  • Christopher F. Nicodemus
    • 8
  • Manuel L. Penichet
    • 1
    • 2
    • 3
    • 4
  1. 1.Division of Surgical Oncology, Department of Surgery, David Geffen School of MedicineUniversity of California, Los AngelesLos AngelesUSA
  2. 2.Department of Microbiology, Immunology, and Molecular GeneticsUniversity of California, Los AngelesCaliforniaUSA
  3. 3.Jonsson Comprehensive Cancer CenterUniversity of California, Los AngelesCaliforniaUSA
  4. 4.The Molecular Biology InstituteUniversity of California, Los AngelesCaliforniaUSA
  5. 5.Department of Obstetrics and GynecologyUniversity of California, Los AngelesCaliforniaUSA
  6. 6.Department of EpidemiologyUniversity of California, Los AngelesCaliforniaUSA
  7. 7.School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina
  8. 8.Advanced Immune Therapeutics, Inc.CharlestownUSA
  9. 9.Momenta Pharmaceuticals, Inc.CambridgeUSA

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