title: Complement dependent cytotoxicity in chronic lymphocytic leukemia: ofatumumab enhances alemtuzumab complement dependent cytotoxicity and reveals cells resistant to activated complement.
abstract: Complement dependent cytotoxicity (CDC) is an important mechanism of action for monoclonal antibodies (mAbs) used in the treatment of chronic lymphocytic leukemia (CLL). We hypothesized that alemtuzumab (ALM) mediated CDC would be increased by the addition of ofatumumab (OFA). CLL cells from 21 previously untreated patients with progressive disease were tested in vitro for mAb binding, complement activation and CDC. The subpopulation of CDC resistant CLL cells was examined for levels of C3b and C5b-9 binding, and expression of complement regulatory proteins. OFA significantly increased complement activation and CDC in ALM-treated CLL cells, suggesting that combining ALM and OFA could improve clinical outcome in patients with CLL. Approximately 10% of CLL cells were resistant to CDC because of lower levels of complement activation or decreased cytotoxicity of activated complement. Improvement of clinical responses will require determining the mechanisms of CDC resistance and developing methods to overcome this problem.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nisar A
authors.initials: NA
authors.lastname: Baig
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Lindorfer
authors.forename: Amy K
authors.initials: AK
authors.lastname: Church
authors.forename: Betsy R
authors.initials: BR
authors.lastname: Laplant
authors.forename: Emily S
authors.initials: ES
authors.lastname: Pavey
authors.forename: Grzegorz S
authors.initials: GS
authors.lastname: Nowakowski
authors.forename: Clive S
authors.initials: CS
authors.lastname: Zent
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003167:Complement Activation; D003179:Complement C3b / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015938:Complement Membrane Attack Complex; D000074323:Alemtuzumab; D003179:Complement C3b; D003165:Complement System Proteins; C527517:ofatumumab