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

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The Oncologist, Vol. 13, No. 9, 954-966, September 2008;

doi:10.1634/theoncologist.2008-0089

The Role of Complement in the Mechanism of Action of Rituximab for B-Cell

Lymphoma: Implications for Therapy

Xuhui Zhoua, Weiguo Hub,c, Xuebin Qinb,c

aChangzheng Hospital, Second Military Medical University, Shanghai, China;

bDepartment of Medicine, Brigham and Women's Hospital, Boston, Massachusetts,

USA; cHarvard Medical School, Laboratory for Translational Research, Cambridge,

Massachusetts, USA

Key Words. Rituximab • CD20 • Mechanism • Resistance • Complement •

B-cell non-Hodgkin's lymphoma

Correspondence: Xuebin Qin, M.D., Ph.D., Harvard Medical School, One Kendall

Square, Building 600, 3rd Floor, Cambridge, Massachusetts 02139, USA. Telephone:

617-621-6102; Fax: 617-621-6148; e-mail: xuebin_qin@...

Received April 9, 2008; accepted for publication August 5, 2008; first published

online in THE ONCOLOGIST Express on September 8, 2008.

Disclosure: The content of this article has been reviewed by independent peer

reviewers to ensure that it is balanced, objective, and free from commercial

bias. No financial relationships relevant to the content of this article have

been disclosed by the authors, planners, independent peer reviewers, or staff

managers.

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

non-Hodgkin's lymphoma (NHL). However, there are also some challenges for us to

overcome: why 50% 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 complement-dependent 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; ( enhance

the ADCC effect through some immunomodulatory cytokines and CR3-binding

β-glucan; and © 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.