Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms

Scand J Immunol. 2000 Jun;51(6):634-41. doi: 10.1046/j.1365-3083.2000.00745.x.

Abstract

Rituximab (IDEC-C2B8, Mabthera(R)) is a chimeric (human-mouse) monoclonal antibody (MoAb) against the B-cell specific CD20-antigen. It has been used for the clinical treatment of non-Hodgkin's lymphomas, but variable clinical results suggest that some lymphoma cells remain resistant. In the present study we have evaluated the relative efficiencies of humoral and cell-mediated effector mechanisms complement-dependent cytotoxicity (CDC), antibody-(ADCC), complement-(CDCC) dependent cellular cytotoxicity and apoptosis on lymphoma cell killing by rituximab. Rituximab activated the cytolytic complement (C) cascade and induced a strong CDC, but the rituximab-triggered ADCC and CDCC were relatively ineffective. The CDC was strongly enhanced by antibodies against the C inhibitor CD59 (protectin). Neutralization of CD55 (DAF) and CD46 (MCP) had a similar but weaker effect. Rituximab also induced apoptosis but in a cell line-dependent fashion. The results strongly emphasize the role of direct CDC as the major, fast and efficient effector mechanism of rituximab. In the immunotherapeutic treatment of B-cell lymphomas, it is important to consider the role of C-regulatory proteins as an escape mechanism of the malignant cells. Our results suggest that the effect of rituximab therapy could be enhanced by combining it with neutralization of CD59.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Murine-Derived
  • Antibody-Dependent Cell Cytotoxicity
  • Antigens, CD / biosynthesis
  • Antigens, CD20 / immunology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / immunology
  • CD55 Antigens / biosynthesis
  • CD59 Antigens / biosynthesis
  • Complement Inactivator Proteins / biosynthesis
  • Complement System Proteins / immunology*
  • Complement System Proteins / metabolism
  • Cytotoxicity Tests, Immunologic
  • Cytotoxicity, Immunologic*
  • Humans
  • Lymphoma, B-Cell / therapy*
  • Membrane Cofactor Protein
  • Membrane Glycoproteins / biosynthesis
  • Rituximab
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Antigens, CD
  • Antigens, CD20
  • Antineoplastic Agents
  • CD46 protein, human
  • CD55 Antigens
  • CD59 Antigens
  • Complement Inactivator Proteins
  • Membrane Cofactor Protein
  • Membrane Glycoproteins
  • Rituximab
  • Complement System Proteins