Blockade of bulky lymphoma-associated CD55 expression by RNA interference overcomes resistance to complement-dependent cytotoxicity with rituximab.
Recently, anti-CD20 (rituximab) and anti-Her2/neu (trastuzumab) antibodies have been developed and applied to the treatment of malignant lymphoma and breast cancer, respectively. However, bulky lymphoma is known to be resistant to rituximab therapy, and this needs to be overcome. Fresh lymphoma cells were collected from 30 patients with non-Hodgkin's lymphoma, the expression of CD20 and CD55 was examined by flow cytometry, and complement-dependent cytotoxicity (CDC) assays were carried out. Susceptibility to CDC with rituximab was decreased in a tumor size-dependent manner (r=-0.895, P<0.0001), but not in a CD20-dependent manner (r=-0.076, P=0.6807) using clinical samples. One complement-inhibitory protein, CD55, contributed to bulky lymphoma-related resistance to CDC with rituximab. A decrease in susceptibility to CDC with rituximab was statistically dependent on CD55 expression (r=-0.927, P<0.0001) and the relationship between tumor size and CD55 expression showed a significant positive correlation (r=0.921, P<0.0001) using clinical samples. To overcome the resistance to rituximab by high expression of CD55 in bulky lymphoma masses, small interfering RNA (siRNA) was designed from the DNA sequence corresponding to nucleic acids 1-380 of the CD55 cDNA. Introduction of this siRNA decreased CD55 expression in the breast cancer cell line SK-BR3 and in CD20-positive cells of patients with recurrent lymphoma; resistance to CDC was also inhibited. This observation gives us a novel strategy to suppress bulky disease-related resistance to monoclonal antibody treatment.
Terui
Yasuhito
Y
Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Sakurai
Takuma
T
Mishima
Yuko
Y
Mishima
Yuji
Y
Sugimura
Natsuhiko
N
Sasaoka
Chino
C
Kojima
Kiyotsugu
K
Yokoyama
Masahiro
M
Mizunuma
Nobuyuki
N
Takahashi
Shunji
S
Ito
Yoshinori
Y
Hatake
Kiyohiko
K
D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018958:CD55 Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000187:drug effects* / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018958:CD55 Antigens; D034741:RNA, Small Interfering; D000069283:Rituximab; D003165:Complement System Proteins