Fey receptor

A Type III allergic reaction occurs when antibodies of the immunoglobulin G class (IgG) form immune complexes which are slowly eliminated and thus may elicit an inflammatory reaction by binding to the Fey receptors of leukocytes resulting in their activation. 

Fc Crystallizable fraction of immunoglobulin molecule Fey Receptor for Fc portion of IgG FeyRI Ig Fc receptor I also known as CD64... 

IgG autoantibody-coated platelets induce Fey receptor-mediated phagocytosis by mononuclear macrophages, predominantly in the spleen and liver. Thrombocytopenia develops as a consequence of megakaryocyte inability to increase platelet production and maintain a normal number of circulating platelets. Currently used treatments are directed at different aspects of the antibody production, platelet sensitization, and the clearance and production cycle.30... 

Several approaches can be taken to determine the function of the different neutrophil Fey receptors during binding to immune complexes ... 

Qiacko et al, 1996). Cell growth is arrested when the type II Fey receptor bl (FcyRIIbl) associates with the B ceU receptor (BCR) by the interaction of their extracellular domains with immune complexes. Clustering FcyRIIbl with BCR induces the phosphorylation of the immimoreceptor tyrosine-based inhibitory motif (ITIM) within the FcyRIIb intracellular tail, which then allows SHIP to bind through its SH2 domain. Recruitment of SHIP to the cell membrane by FcyRIIb p-ITIM is believed to block extracellular uptake and cell growth via the inositol 5-phosphatase activity of SHIP. 

Sammy, G., Koncz, G. andGergely, J., 1996, Human type II Fey receptors inhibit B cell activation by interacting with the p2l -dependent pathway. 7. Biol. Chem. 271 30499-30504. 

An understanding of Fey 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 Fey receptor affinity or introduction of Fey receptor-reengineered monoclonal antibody designed to enhance binding to the Fey receptor. 

This chapter reviews our current understanding of the mechanism of action of monoclonal antibody (especially rituximab), as well as the role of Fey receptor and Fey 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 Fey 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. 

The affinity of host effector cells to rituximab has been known to mediate the ADCC activity of effector cells (5). In addition, the Fey receptor polymorphism has been found to affect the binding capacities and clinical responses to rituximab (5,6). This issue will be discussed later in this chapter. 

Alemtuzumab has shown impressive results in refractory or relapsed CLL as well as up-front therapy for untreated CLL (35). The use of alemtuzumab to eradicate minimal residual disease of CLL is also reasonable (36). The role of Fey receptor polymorphisms on the clinical activity of alemtuzumab for CLL has not been extensively studies and will be discussed later. 

These two reports suggest that the encouraging efficacy of CHOP therapy followed by rituximab for FL patients may be independent of Fey receptor polymorphism (51,52). 

Engineered IgG antibodies have been constructed with altered affinity to human Fey receptors and altered potency in vitro and in animal models [14, 31-33]. Mutations of critical residues in the Fc region (CH2 domain or the hinge region joining CH1 and CH2) have enhanced or decreased antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [33-37]. In addition, alterations in residues located at the CH2 domain of I gC, i involved in binding with Clq protein, a component of the complement activation cascade, resulted in a significant increase in CDC activity [34, 35]. 

Koncz, G., Pecht, I., Gergely, J., and Sarmay, G., 1999, Fey receptor mediated inhibition of human B cell activation the role of SHP-2 phosphatase. Eur. J. Immunol. 29 1980-1989. 

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