Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL.
Monoclonal antibodies (MAbs) form a central part of chronic lymphocytic leukaemia (CLL) treatment. We therefore evaluated whether complement defects in CLL patients reduced the induction of complement-dependent cytotoxicity (CDC) by using anti-CD20 MAbs rituximab (RTX) and ofatumumab (OFA). Ofatumumab elicited higher CDC levels than RTX in all CLL samples examined, particularly in poor prognosis cohorts (11q- and 17p-). Serum sample analyses revealed that 38.1% of patients were deficient in one or more complement components, correlating with reduced CDC responses. Although a proportion of patients with deficient complement levels initially induced high levels of CDC, on secondary challenge CDC activity in sera was significantly reduced, compared with that in normal human serum (NHS; P<0.01; n=52). In addition, a high CLL cell number contributed to rapid complement exhaustion. Supplementing CLL serum with NHS or individual complement components, particularly C2, restored CDC on secondary challenge to NHS levels (P<0.0001; n=9). In vivo studies revealed that complement components were exhausted in CLL patient sera post RTX treatment, correlating with an inability to elicit CDC. Supplementing MAb treatment with fresh-frozen plasma may therefore maintain CDC levels in CLL patients with a complement deficiency or high white blood cell count. This study has important implications for CLL patients receiving anti-CD20 MAb therapy.
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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Middleton
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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Cosimo
Department of Haematology, Western General Hospital, Edinburgh, UK.
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Dobbin
1] Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK [2] Department of Haematology, Royal Alexandra Hospital, Paisley, UK.
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McCaig
GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex, UK.
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Clarke
GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex, UK.
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Brant
Department of Haematology, West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK.
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Leach
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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Michie
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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Wheadon
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20 / Q000276:immunology*; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000172:deficiency*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000628:therapy*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018951:Antigens, CD20; D003165:Complement System Proteins; C527517:ofatumumab