TY - JOUR
T1 - Enhanced cytotoxicity of Rituximab following genetic and biochemical disruption of glycosylphosphatidylinositol anchored proteins
AU - Nagajothi, Nagaprasad
AU - Matsui, William H.
AU - Mukhina, Galina L.
AU - Brodsky, Robert A.
N1 - Funding Information:
Grant support: RAB is a Clinical Scholar of the Leukemia and Lymphoma Society of America. WHM is a Fellow Scholar of the Leukemia and Lymphoma Society of America. Supported in part by the National Institute of Health grant P50CA096888-01.
PY - 2004/4
Y1 - 2004/4
N2 - Rituximab, an anti-CD20 monoclonal antibody used to treat B cell lymphoproliferative disorders and autoimmune diseases, kills cells through complement dependent cytotoxicity, antibody-dependent cellular toxicity and apoptosis. A mechanism of resistance to rituximab is upregulation of the complement regulatory proteins, CD59 and CD55. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic disorder caused by PIGA mutations that lead to a loss of all glycosylphospatidylinositol (GPI)-anchored proteins including, CD55 and CD59. We compared the cytotoxic activity of rituximab against a PNH B cell line, LD-, and the isogenic cell line LD- PIGA+ in which GPI-anchor expression was restored by stable transfection of PIGA. The PNH cell line was more sensitive to rituximab-mediated killing than the LD- PIGA+ cells. Biochemical disruption of GPI anchors with phosphatidylinositol specific phospholipase C (PIPLC), a phospholipase that cleaves GPI-anchored proteins, also increased rituximab-mediated killing. Thus, genetic and biochemical interruption of GPI anchor proteins augments sensitivity to rituximab.
AB - Rituximab, an anti-CD20 monoclonal antibody used to treat B cell lymphoproliferative disorders and autoimmune diseases, kills cells through complement dependent cytotoxicity, antibody-dependent cellular toxicity and apoptosis. A mechanism of resistance to rituximab is upregulation of the complement regulatory proteins, CD59 and CD55. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic disorder caused by PIGA mutations that lead to a loss of all glycosylphospatidylinositol (GPI)-anchored proteins including, CD55 and CD59. We compared the cytotoxic activity of rituximab against a PNH B cell line, LD-, and the isogenic cell line LD- PIGA+ in which GPI-anchor expression was restored by stable transfection of PIGA. The PNH cell line was more sensitive to rituximab-mediated killing than the LD- PIGA+ cells. Biochemical disruption of GPI anchors with phosphatidylinositol specific phospholipase C (PIPLC), a phospholipase that cleaves GPI-anchored proteins, also increased rituximab-mediated killing. Thus, genetic and biochemical interruption of GPI anchor proteins augments sensitivity to rituximab.
KW - Complement dependent cytoxicity
KW - GPI-anchored proteins
KW - Mechanism of action
KW - Rituximab
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U2 - 10.1080/10428190310001625700
DO - 10.1080/10428190310001625700
M3 - Article
C2 - 15160958
AN - SCOPUS:1342266138
SN - 1042-8194
VL - 45
SP - 795
EP - 800
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 4
ER -