This cytotoxic reaction can be modeled in vitro and ALM in the presence of complement has previously been shown to rapidly kill 70%–80% of CLL cells in suspension culture.

The rapid and extensive clearance of circulating CLL cells after initiation of ALM therapy in patients is likely to be substantially mediated by C3b-opsonization and CDC. However, the functional importance of each of these mechanisms for these mAb in the treatment of CLL is still uncertain. ALM, OFA, and RTX utilize a human IgG1 heavy chain constant region and are capable of activating antibody dependent cellular cytotoxicity (ADCC), and there is considerable data to support an important role for ADCC in the mechanism of action of these mAbs. In contrast there is extensive data showing that CDC is an important mechanism of action in CLL for ALM and OFA but not for RTX. There is considerable in vitro data showing that ALM and RTX do not directly induce appreciable apoptosis in CLL cells. The potential cytotoxic mechanisms of mAb include complement dependent cytotoxicity (CDC), cell mediated cytotoxicity, and direct induction of cell death by apoptosis or autophagy. However, despite the demonstrated efficacy of these mAb in the treatment of CLL, we still do not have a clear understanding of their mechanisms of action or the reasons for CLL cell resistance to mAb mediated cytotoxicity. The recently FDA-approved human anti-CD20 mAb ofatumumab (OFA) has appreciable activity in the treatment of CLL and could be an important additional drug in combination therapy. Rituximab (RTX, specific for CD20) based chemoimmunotherapy has markedly increased response rates in the treatment of CLL and addition of RTX to fludarabine and cyclophosphamide increases overall survival after initial treatment of progressive CLL. The CD52 specific mAb alemtuzumab (ALM) is highly effective in the treatment of CLL and is especially important in the management of patients with TP53 defective or purine analogue refractory disease. Monoclonal antibodies (mAb) that target certain proteins on B cells are valuable drugs for the treatment of chronic lymphocytic leukemia (CLL).

Improvement of clinical responses will require determining the mechanisms of CDC resistance and developing methods to overcome this problem. Approximately 10% of CLL cells were resistant to CDC because of lower levels of complement activation or decreased cytotoxicity of activated complement. 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. The subpopulation of CDC resistant CLL cells was examined for levels of C3b and C5b-9 binding, and expression of complement regulatory proteins. CLL cells from 21 previously untreated patients with progressive disease were tested in vitro for mAb binding, complement activation, and CDC. We hypothesized that alemtuzumab (ALM) mediated CDC would be increased by addition of ofatumumab (OFA). Complement dependent cytotoxicity (CDC) is an important mechanism of action for monoclonal antibodies (mAb) used in the treatment of chronic lymphocytic leukemia (CLL).

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