Complement-dependent cytotoxicity induced by therapeutic antibodies in B-cell acute lymphoblastic leukemia is dictated by target antigen expression levels and augmented by loss of membrane-bound complement inhibitors

Abstract

To optimally utilize therapeutic monoclonal antibodies in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) understanding their mechanisms of action and the factors influencing these mechanisms is required. We show strong correlations between target antigen expression levels and sensitivity to complement-dependent cytotoxicity (CDC) induced by rituximab, ofatumumab, or alemtuzumab in a panel of cell lines derived from primary B-ALL cells and in primary B-ALL samples. Simultaneous loss of expression of membrane-bound complement regulatory proteins (mCRP) CD55 and CD59 due to glycophosphatidylinositol-anchor deficiency, significantly increased sensitivity to CDC. Accordingly, induced increase in CD55 or CD59 expression protected cells against CDC. The extent of protection co-depended on antigen expression and antibody concentration. In contrast, natural variation in mCRP expression could not be used as a single factor to predict sensitivity to CDC. In conclusion, sensitivity of B-ALL cells to CDC was predominantly determined by antibody concentration and target antigen expression.

Keywords:

• Complement-dependent cytotoxicity
• B-cell acute lymphoblastic leukemia
• membrane-bound complement regulatory proteins
• antibody therapy
• CD55
• CD59

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at http://10.1080/10428194.2017.1281411.

Funding

This work was supported by the ‘Frank Sanderse Stichting’ and the ‘Doelfonds Leukemie van de Bontius Stichting’.