Current combination
therapies elicit high response rates in B cell
malignancies, often using CD20
antibodies as the backbone of
therapy. However, many patients eventually relapse or develop progressive disease. Therefore, novel CD20
antibodies combining multiple effector mechanisms were generated. To study whether neutrophil-mediated destruction of B cell
malignancies can be added to the arsenal of effector mechanisms, we chimerized a panel of five previously described murine CD20
antibodies to the human
IgG1,
IgA1 and
IgA2 isotype. Of this panel, we assessed in vitro antibody-dependent cell-mediated cytotoxicity (ADCC),
complement-dependent cytotoxicity (CDC) and direct cell death induction capacity and studied the efficacy in two different in vivo mouse models.
IgA antibodies outperformed
IgG1 antibodies in neutrophil-mediated killing in vitro, both against CD20-expressing cell lines and primary patient material. In these assays, we observed loss of CD19 with both
IgA and
IgG antibodies. Therefore, we established a novel method to improve the assessment of B-cell depletion by CD20
antibodies by including CD24 as a stable cell marker. Subsequently, we demonstrated that only
IgA antibodies were able to reduce B cell numbers in this context. Additionally,
IgA antibodies showed efficacy in both an intraperitoneal
tumor model with EL4 cells expressing huCD20 and in an adoptive transfer model with huCD20-expressing B cells. Taken together, we show that
IgA, like
IgG, can induce ADCC and CDC, but additionally triggers neutrophils to kill (malignant) B cells. We conclude that
antibodies of the
IgA isotype offer an attractive repertoire of effector mechanisms for the treatment of CD20-expressing
malignancies.