Bispecific antibody-targeted phagocytosis of HER-2/neu expressing tumor cells by myeloid cells activated in vivo

Paul K. Wallace, Peter A. Kaufman, Lionel D. Lewis, Tibor Keler, Alice L. Givan, Jan L. Fisher, Mary G. Waugh, Andrea E. Wahner, Paul M. Guyre, Michael W. Fanger, Marc S. Ernstoff

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Studies from our laboratory and others have established that both mononuclear phagocytes and neutrophils mediate very efficient cytotoxicity when targeted through Fc receptors using a suitable monoclonal or bispecific antibody (BsAb). Cross-linking an Fc receptor for IgG (FcγR) triggers multiple anti-tumor activities including superoxide generation, cytokine and enzyme release, phagocytosis and antibody-dependent cellular cytotoxicity (ADCC). In this report, using unfractionated leukocytes and two color flow cytometric analysis, we describe the phagocytic capacity of peripheral blood polymorphonuclear cells (PMN) and monocytes isolated from patients enrolled in a phase I clinical trial of MDX-H210 given in combination with IFNγ. MDX-H210 is a BsAb targeting the myeloid trigger molecule FcγRI and the HER-2/neu proto-oncogene product overexpressed on a variety of adenocarcinomas. In this trial, cohorts of patients received escalating doses of MDX-H210 3 times per week for 3 weeks. Interferon-γ (IFNγ) was given 24 h prior to each BsAb infusion. Our results demonstrate that monocytes from these patients were inherently capable of phagocytosing the HER-2/neu positive SK-BR-3 cell line and that addition of MDX-H210 into the assay significantly enhanced the number of targets phagocytosed. Two days after administration of an immunologically active dose of MDX-H210 (10 mg/m2), monocytes from these patients were able to phagocytose greater amounts of target cell material, indicating that these cells remained armed with functionally sufficient BsAb for at least 48 h. PMN from these patients very efficiently mediated phagocytosis through FcγRI after being treated with IFNγ, but not before. We conclude that phagocytosis is not only an efficient mechanism of myeloid cell-mediated cytotoxicity, but may also be a mechanism by which antigens from phagocytosed cells can enter a professional antigen presenting cell for processing and presentation.

Original languageEnglish (US)
Pages (from-to)167-182
Number of pages16
JournalJournal of Immunological Methods
Volume248
Issue number1-2
DOIs
StatePublished - Feb 1 2001

Keywords

  • ADCC
  • Bispecific antibody
  • Fc receptor for IgG
  • HER-2/neu
  • Phagocytosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Wallace, P. K., Kaufman, P. A., Lewis, L. D., Keler, T., Givan, A. L., Fisher, J. L., Waugh, M. G., Wahner, A. E., Guyre, P. M., Fanger, M. W., & Ernstoff, M. S. (2001). Bispecific antibody-targeted phagocytosis of HER-2/neu expressing tumor cells by myeloid cells activated in vivo. Journal of Immunological Methods, 248(1-2), 167-182. https://doi.org/10.1016/S0022-1759(00)00350-1