Combination of two anti‐CD5 monoclonal antibodies synergistically induces complement‐dependent cytotoxicity of chronic lymphocytic leukaemia cells

Summary The treatment of chronic lymphocytic leukaemia ( CLL ) has been improved by introduction of monoclonal antibodies (m A bs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD 5 and CD 23 along with CD 19 and CD 20, hence anti‐ CD 5 A bs that engage secondary effector functions represent an attractive opportunity for CLL treatment. Here, a repertoire of m A bs against human CD 5 was generated and tested for ability to induce complement‐dependent cytotoxicity ( CDC ) and antibody‐dependent cell‐mediated cytotoxicity ( ADCC ) both as single m A bs and combinations of two m A bs against non‐overlapping epitopes on human CD 5. The results demonstrated that combinations of two m A bs significantly increased the level of CDC compared to the single m A bs, while no enhancement of ADCC was seen with anti‐ CD 5 m A b combinations. High levels of CDC and ADCC correlated with low levels of A b‐induced CD 5 internalization and degradation. Importantly, an anti‐ CD 5 m A b combination enhanced CDC of CLL cells when combined with the anti‐ CD 20 m A bs rituximab and ofatumumab as well as with the anti‐ CD 52 m A b alemtuzumab. These results suggest that an anti‐ CD 5 m A b combination inducing CDC and ADCC may be effective alone, in combination with m A bs against other targets or combined with chemotherapy for CLL and other CD 5‐expressing haematological or lymphoid malignancies.