Introduction

Monoclonal antibodies that target various specific antigens can be used to kill the tumor cells expressing specific antigens. To our knowledge, five kinds of monoclonal antibodies have been approved by the Food and Drug Administration (FDA) of the United States for the treatment of hematologic malignancies: rituximab (Rituxan® or MabThera®; IDEC pharmaceuticals Corp, San Diego, CA, USA, and Genentech, San Fransisco, CA, USA), alemtuzumab (Campath® or MabCAMPATH®, Genzyme, Cambridge, MA, USA, and Schering AG, Berlin, Germany), ibritumomab tiuxtan (Zevaline®, Biogen IDEC, San Diego, CA, USA), tositumomab (Bexxar®, Corixa and GlaxoSmithKline, Seattle, WA, USA) and gemtuzumab ozogamicin (Mylotarg®, Wyeth, Madison, NJ, USA).

A major breakthrough in the treatment of lymphoid malignancies was the discovery of monoclonal antibody activity, especially that of rituximab. Rituximab was the first monoclonal antibody approved by the U.S., FDA for the treatment of relapsed follicular lymphoma (1), and it has now been extensively used for the treatment of various lymphoid neoplasm which express CD20 antigen. Its efficacy has been also demonstrated against diffuse large B-cell lymphoma when administered as a combination regimen such as rituximab plus CHOP (R-CHOP) chemotherapy (2).

The precise mechanism of rituximab, as well as other monoclonal antibodies, is still incompletely understood despite extensive investigations. To our current knowledge, the mechanism of rituximab activity includes antibody-dependent cellular cytotoxic-ity (ADCC), complement dependent cytotoxicity (CDC). and a direct pro-apoptotic effect (3,4).

There are two major factors predisposing to resistance to monoclonal antibody therapy. One is a tumor-related factor such as antigen loss, complement resistance antigen expression, intrinsic resistance, or tumor burden. Besides tumor-related factors, growing evidence has indicated that patient-related factors may account for the different responses of the patients to monoclonal antibody therapy. For example, differences in ADCC or CDC function according to individuals may increase our understanding of resistance to monoclonal antibody therapy. The affinity of host effector cells to monoclonal antibody via Fcy receptor III (FcyRIII; CD16) or Fcy receptor II (FcyRII; CD32) has been known to mediate the ADCC activity of effector cells (5).

The importance of the Fc receptor to the action mechanism of monoclonal antibody is derived from the following facts. Immunoglobulin has two binding sites: binding sites to antigen and to Fcy receptor or complements. Although the antigen-binding site is important for binding to tumor cells expressing a specific antigen, the binding affinity to Fcy receptor is known to be correlated with the efficacy of monoclonal antibody, especially rituximab. Growing evidence suggests that the single nucleotide polymorphisms of Fcy receptor genes are associated with various binding capacities and different clinical responses to monoclonal antibody therapy (5,6).

An understanding of Fcy receptor gene polymorphism explains why some patients do not respond to monoclonal antibody, and it may broaden our understanding of monoclonal antibody activity and improve treatment outcomes in the future. Specific strategies include modulation of Fcy receptor affinity or introduction of Fcy receptor-reengineered monoclonal antibody designed to enhance binding to the Fcy receptor.

This chapter reviews our current understanding of the mechanism of action of monoclonal antibody (especially rituximab), as well as the role of Fcy receptor and Fcy receptor gene polymorphisms, and their impact on treatment outcomes in hematologic malignancies including follicular lymphoma (FL), diffuse large B-cell lymphoma (DL-BCL), Waldenstrom's macroglobulinemia (WM), and chronic lymphocytic leukemia (CLL).

We will discuss the approaches augmenting the clinical activity of monoclonal antibody, especially focusing on Fcy receptor re-engineered monoclonal antibody. A better understanding of how monoclonal antibody acts in vivo will lead to the development of new, more effective therapeutic strategies.

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