Glyco-engineered anti-EGFR mAb elicits ADCC by NK cells from colorectal cancer patients irrespective of chemotherapy
| Autor: | Thomas V.A. Murray, David Oppenheim, Anton Belousov, Farzin Farzaneh, David Malone, B. S. Choi, Eunice Amofah, Alexandre Passioukov, Laura McLaughlin, C. Pena-Murillo, Christian Gerdes, Pablo Umana, S. Allan, A. Etuk, Paul Ross, Roberto Spreafico |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
GA201 Colorectal cancer medicine.drug_class medicine.medical_treatment colorectal cancer chemical and pharmacologic phenomena Antibodies Monoclonal Humanized GPI-Linked Proteins Monoclonal antibody Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Humans Molecular Diagnostics Glycoproteins Antibody-dependent cell-mediated cytotoxicity Chemotherapy Cetuximab biology business.industry Receptors IgG Antibody-Dependent Cell Cytotoxicity hemic and immune systems medicine.disease Oxaliplatin ErbB Receptors Killer Cells Natural glyco-engineering Oncology monoclonal antibody Case-Control Studies Immunoglobulin G Monoclonal Immunology biology.protein Antibody Colorectal Neoplasms K562 Cells ADCC business medicine.drug |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Background: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC), and is correlated with poor prognosis, making it an attractive target for monoclonal antibody (mAb) therapy. A component of the therapeutic efficacy of IgG1 mAbs is their stimulation of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells bearing the CD16 receptor. As NK cells are functionally impaired in cancer patients and may be further compromised upon chemotherapy, it is crucial to assess whether immunotherapeutic strategies aimed at further enhancing ADCC are viable. Methods: CRC patients before, during and after chemotherapy were immunophenotyped by flow cytometry for major white blood cell populations. ADCC-independent NK cell functionality was assessed in cytotoxicity assays against K562 cells. ADCC-dependent killing of EGFR+ A431 cancer cells by NK cells was measured with a degranulation assay where ADCC was induced by GA201, an anti-EGFR mAb glyco-engineered to enhance ADCC. Results: Here, we confirm the observation that NK cells in cancer patients are dysfunctional. However, GA201 was able to induce robust NK cell-dependent cytotoxicity in CRC patient NK cells, effectively overcoming their impairment. Conclusions: These findings support the evaluation of the therapeutic potential of GA201 in combination with chemotherapy in CRC patients. |
| Databáze: | OpenAIRE |
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