Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies

The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to t reat patients with various B-cell tumors, including patients with plasma ce ll dyscrasias who have CD20(+) disease. Many patients with CD20(+) disease have either primary unresponsive disease or progress after initially respon ding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determ ined whether tumor cells express antigens that block complement-mediated ly sis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby con tribute to rituximab resistance. We demonstrate that expression of the comp lement regulator CD59 is associated with resistance to rituximab-mediated c omplement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) c ell lines. Moreover, neutralization of CD59 using a blocking monoclonal ant ibody reversed resistance to rituximab-mediated complement lysis of CD20(+) CD59(++) ARH-77 MM cells. In addition, we demonstrate the presence of CD5 9 and rituximab binding on viable tumor cells from patients with MM and Wal denstrom's macroglobulinemia with progressive disease despite rituximab the rapy. Last, we also examined MM and NHL B-cell lines, as well as patient tu mor cells, for the expression of other antigens that may have a role in blo cking ADCC activity, such as Fas ligand (FasL), MUC1, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularl y CD59 and antigens that may block ADCC, are present on various B-cell tumo rs and associated with rituximab resistance in patients. A prospective, cli nical study is assessing the role of these antigens in mediating rituximab resistance.