Glyco-engineered anti-EGFR mAb elicits ADCC by NK cells from colorectal cancer patients irrespective of chemotherapy.
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.
1] Comprehensive Biomedical Research Centre, King's College London, King's Health Partners, London, UK [2] Experimental Cancer Medicine Centre, King's College London, King's Health Partners, London, UK [3] Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
D E
DE
Oppenheim
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
R
R
Spreafico
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
A
A
Etuk
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
D
D
Malone
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
E
E
Amofah
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
C
C
Peña-Murillo
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
T
T
Murray
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
L
L
McLaughlin
Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
B S
BS
Choi
Department of Medical Oncology, Guy's and St Thomas' Hospital, King's College London School of Medicine, King's Health Partners, 4th Floor Thomas Guy House, Guy's Hospital, St Thomas Street, London SE1 9RT, UK.
S
S
Allan
Roche Diagnostics GmbH, Nonnenwald 2, Penzberg 82377, Germany.
A
A
Belousov
Roche Glycart AG, Wagistrasse 18, Schlieren 8952, Switzerland.
A
A
Passioukov
Roche Glycart AG, Wagistrasse 18, Schlieren 8952, Switzerland.
C
C
Gerdes
Roche Glycart AG, Wagistrasse 18, Schlieren 8952, Switzerland.
P
P
Umaña
1] Comprehensive Biomedical Research Centre, King's College London, King's Health Partners, London, UK [2] Experimental Cancer Medicine Centre, King's College London, King's Health Partners, London, UK [3] Department of Haematological Medicine, King's College London School of Medicine, King's Health Partners, 123 Coldharbour Lane, London SE5 9NU, UK.
F
F
Farzaneh
1] Comprehensive Biomedical Research Centre, King's College London, King's Health Partners, London, UK [2] Experimental Cancer Medicine Centre, King's College London, King's Health Partners, London, UK [3] Department of Medical Oncology, Guy's and St Thomas' Hospital, King's College London School of Medicine, King's Health Partners, 4th Floor Thomas Guy House, Guy's Hospital, St Thomas Street, London SE1 9RT, UK.
P
P
Ross
D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D066246:ErbB Receptors / Q000276:immunology*; D058851:GPI-Linked Proteins / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology* / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology
D061067:Antibodies, Monoclonal, Humanized; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D007074:Immunoglobulin G; D017452:Receptors, IgG; C512478:EGFR protein, human; D066246:ErbB Receptors; C569293:imgatuzumab