Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia.

Abstract

Complement plays an important role in the immunotherapeutic action of the anti-CD20 mAb rituximab, and therefore we investigated whether complement might be the limiting factor in rituximab therapy. Our in vitro studies indicate that at high cell densities, binding of rituximab to human CD20(+) cells leads to loss of complement activity and consumption of component C2. Infusion of rituximab in chronic lymphocytic leukemia patients also depletes complement; sera of treated patients have reduced capacity to C3b opsonize and kill CD20(+) cells unless supplemented with normal serum or component C2. Initiation of rituximab infusion in chronic lymphocytic leukemia patients leads to rapid clearance of CD20(+) cells. However, substantial numbers of B cells, with significantly reduced levels of CD20, return to the bloodstream immediately after rituximab infusion. In addition, a mAb specific for the Fc region of rituximab does not bind to these recirculating cells, suggesting that the rituximab-opsonized cells were temporarily sequestered by the mononuclear phagocytic system, and then released back into the circulation after the rituximab-CD20 complexes were removed by phagocytic cells. Western blots provide additional evidence for this escape mechanism that appears to occur as a consequence of CD20 loss. Treatment paradigms to prevent this escape, such as use of engineered or alternative anti-CD20 mAbs, may allow for more effective immunotherapy of chronic lymphocytic leukemia.

• Authors: Adam D Kennedy, Paul V Beum, Michael D Solga, David J DiLillo, Margaret A Lindorfer, Charles E Hess, John J Densmore, Michael E Williams, Ronald P Taylor
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 172 Issue 5 Pg. 3280-8 (Mar 01 2004) ISSN: 0022-1767 [Print] United States
• PMID: 14978136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Complement Inactivator Proteins
• Opsonin Proteins
• Rituximab
• Complement C3b
• Complement System Proteins

Topics

• Antibodies, Monoclonal (administration & dosage, metabolism, pharmacology)
• Antibodies, Monoclonal, Murine-Derived
• Antibody-Dependent Cell Cytotoxicity (immunology)
• Antigens, CD20 (biosynthesis, blood, immunology, metabolism)
• B-Lymphocytes (immunology, metabolism)
• Binding Sites, Antibody
• Cell Line, Tumor
• Complement C3b (metabolism)
• Complement Inactivator Proteins (administration & dosage, pharmacology)
• Complement Pathway, Classical (immunology)
• Complement System Proteins (biosynthesis, metabolism)
• Humans
• Infusions, Intravenous
• Leukemia, Lymphocytic, Chronic, B-Cell (immunology, pathology, therapy)
• Opsonin Proteins (metabolism)
• Rituximab
• Serum (physiology)