CD52 over-expression affects rituximab-associated complement-mediated cytotoxicity but not antibody-dependent cellular cytotoxicity: preclinical evidence that targeting CD52 with alemtuzumab may reverse acquired resistance to rituximab in non-Hodgkin lymphoma

Leuk Lymphoma. 2007 Dec;48(12):2424-36. doi: 10.1080/10428190701647879.

Abstract

In an attempt to define mechanisms by which B-cell non-Hodgkin lymphoma (NHL) may escape rituximab immunotherapy, we developed several rituximab-resistant cell lines (RRCL) generated from the rituximab-sensitive cell lines (RSCL) Raji and RL. Rituximab resistance was associated with CD20 downregulation and upregulation of CD52 and the complement inhibitory proteins (CIPs) CD55 and CD59. No significant alemtuzumab-associated complement-mediated cell lysis (CMC) or antibody-dependent cellular cytotoxicity (ADCC) was demonstrated in RSCL. In contrast, in vitro exposure of RRCL to alemtuzumab resulted in a significant degree of CMC and ADCC. Of note, in vitro blocking of CD52 with anti-CD52 F(ab')(2) fractions in RRCL improved rituximab-associated CMC as compared to unblocked RRCL. Our current data provides a basis for further evaluation of alemtuzumab-based clinical trials for patients with rituximab-resistant NHL.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alemtuzumab
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal, Murine-Derived
  • Antibodies, Neoplasm / therapeutic use*
  • Antibody-Dependent Cell Cytotoxicity*
  • Antigens, CD / analysis
  • Antigens, CD20 / analysis
  • Antigens, Neoplasm / analysis
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis
  • CD52 Antigen
  • Cell Line, Tumor
  • Complement System Proteins / immunology*
  • Cytotoxicity, Immunologic
  • Drug Resistance, Neoplasm
  • Glycoproteins / analysis
  • Glycoproteins / antagonists & inhibitors*
  • Histocompatibility Antigens Class II / analysis
  • Humans
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / immunology
  • Rituximab

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Monoclonal, Murine-Derived
  • Antibodies, Neoplasm
  • Antigens, CD
  • Antigens, CD20
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • CD52 Antigen
  • CD52 protein, human
  • Glycoproteins
  • Histocompatibility Antigens Class II
  • Alemtuzumab
  • Rituximab
  • Complement System Proteins