Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL

Middleton, O., Cosimo, E., Dobbin, E., McCaig, A.M., Clarke, C., Brant, A.M., Leach, M.T., Michie, A.M. and Wheadon, H. (2015) Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL. Leukemia, 29(1), pp. 107-114. (doi:10.1038/leu.2014.146) (PMID:24787488)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dobbin, Dr Edwina and Michie, Dr Alison and Mccaig, Dr Alison and Cosimo, Dr Emilio and Wheadon, Dr Helen
Authors: Middleton, O., Cosimo, E., Dobbin, E., McCaig, A.M., Clarke, C., Brant, A.M., Leach, M.T., Michie, A.M., and Wheadon, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Leukemia
Publisher:Nature Publishing Group
ISSN:0887-6924
ISSN (Online):1476-5551
Copyright Holders:Copyright © 2015 Macmillan Publishers Limited
First Published:First published in Leukemia 29(1):107-114
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES