The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy

Abstract

Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell nonHodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why ϳ50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complementdependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding ␤-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed. The Oncologist 2008;13: 954 -966

Complement factor H-derived short consensus repeat 18-20 enhanced complement-dependent cytotoxicity of ofatumumab on chronic lymphocytic leukemia cells

“…10 In the context of non-Hodgkin's lymphoma and CLL, the membranebound RCA (mRCA) CD55 and CD59 have been studied in depth and were identified as important players in protecting these malignant cells against CDC. [11][12][13][14][15][16][17][18] In addition to the mRCA mentioned above, fluid-phase RCA, especially factor H (fH) might potentially be involved in the resistance of CLL cells to antibody-induced CDC. This factor has already been demonstrated to be important in protecting different solid tumors (breast cancer, prostate cancer, lung cancer, etc.)…”

Application of a novel inhibitor of human CD59 for the enhancement of complement-dependent cytolysis on cancer cells

“…When cancer therapeutic Abs activate the so-called classical complement pathway, they trigger the formation of the membrane attack complex on cancer cells, leading to the killing of cancer cells through CDC. 3 CD59, a critical membrane complement regulator, inhibits membrane attack complex formation by binding to the 8a and 9 (C8a and C9) complement proteins. [4][5][6] CD59 is universally expressed in normal cells and highly expressed in many kinds of cancer cells, including NHL and chronic lymphocytic leukemia (CLL).…”

“…[4][5][6] CD59 is universally expressed in normal cells and highly expressed in many kinds of cancer cells, including NHL and chronic lymphocytic leukemia (CLL). 3 Extensive clinical and experimental evidence indicates that CD59 is highly effective at protecting NHL and CLL cells from Ab (rituximab or ofatumumab)-mediated CDC. [7][8][9][10][11][12][13][14][15][16][17][18][19] Many in vivo and in vitro studies indicate that CDC plays a critical role and also interacts synergistically with Ab-dependent cell cytotoxicity in rituximab therapy.…”

“…[7][8][9][10][11][12][13][14][15][16][17][18][19] Many in vivo and in vitro studies indicate that CDC plays a critical role and also interacts synergistically with Ab-dependent cell cytotoxicity in rituximab therapy. 3 To further enhance CDC activity, the human IgG1 anti-CD20 mAb ofatumumab has been developed as another new mAb therapeutic. 20 Ofatumumab has shown better activity for the treatment of relapsed CLL compared to the activity associated with rituximab.…”

The good and evil of complement activation in HIV-1 infection

“…The complement system consists of about 30 soluble and membrane-bound proteins and is activated by three distinct pathways either on the pathogen surface or in the plasma. [1][2][3] The classical pathway is triggered by antigen-bound Ab molecules and is initiated by the binding of the Ab's Fc part to the C1 component. 4 The alternative pathway is a humoral component of the immune system's natural defense against infections and is activated by cleavage of C3 and then C5.…”