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.
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.
Cruz
Raymond I
RI
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Hernandez-Ilizaliturri
Francisco J
FJ
Olejniczak
Scott
S
Deeb
George
G
Knight
Joy
J
Wallace
Paul
P
Thurberg
Beth L
BL
Kennedy
William
W
Czuczman
Myron S
MS
D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000032:analysis; D018951:Antigens, CD20 / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D000074301:CD52 Antigen; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D000074323:Alemtuzumab; D000069283:Rituximab; D003165:Complement System Proteins