Enhanced cytotoxicity of Rituximab following genetic and biochemical disruption of glycosylphosphatidylinositol anchored proteins

Nagaprasad Nagajothi, William H. Matsui, Galina L. Mukhina, Robert A Brodsky

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)795-799
Number of pages5
JournalLeukemia and Lymphoma
Volume45
Issue number4
DOIs
StatePublished - Apr 2004

Fingerprint

Glycosylphosphatidylinositols
Molecular Biology
Paroxysmal Hemoglobinuria
Proteins
Cell Line
B-Lymphocytes
Phosphoinositide Phospholipase C
Lymphoproliferative Disorders
Phospholipases
Autoimmune Diseases
Transfection
Rituximab
Complement System Proteins
Up-Regulation
Monoclonal Antibodies
Apoptosis
Mutation
Antibodies

Keywords

  • Complement dependent cytoxicity
  • GPI-anchored proteins
  • Mechanism of action
  • Rituximab

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Enhanced cytotoxicity of Rituximab following genetic and biochemical disruption of glycosylphosphatidylinositol anchored proteins. / Nagajothi, Nagaprasad; Matsui, William H.; Mukhina, Galina L.; Brodsky, Robert A.

In: Leukemia and Lymphoma, Vol. 45, No. 4, 04.2004, p. 795-799.

Research output: Contribution to journalArticle

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