Anti-tumor MAb can carry out highly effective tu-moricidal functions both in vitro and in vivo; these include signaling through receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-mediated cytotoxicity (CMC) (Cheung 2004). MAb vary in their ability to induce downstream effects. For example, MAb 3F8 is unique among anti-GD2 antibodies in its ability to induce apoptosis among EL4 murine lymphoma cells (Tom-linson et al., unpublished results). MAb can also block receptor functions (e.g.,EGF-R) (Mendelsohn 2003), and vascular endothelial growth factor receptor (VEGF-R) (Prewett et al. 1999) by interfering with binding of the natural ligands.
There are three types of IgG Fc receptors (FcgR): FcgRI (CD64); FcgRII (CD32); and low-affinity FcgRIII (CD 16; Ravetch and Bolland 2001). Most FcgRs are of the activating type except for the inhibitory receptor FcgRIIB. Recent correlation of FcgRIIIA polymorphism with clinical response to rituximab suggests that IgG affinity for Fc receptor can influence anti-tumor response in patients (Cartron et al. 2002; Kimberly et al. 2002). Neuroblastoma cells are effectively killed by NK lymphocytes, granulocytes, and activated monocytes in vitro in the presence of specific MAb. Chimeric hIgG1 specific for GD2 (ch14.18) fused to GM-CSF depends on FcgRII in neutrophil ADCC (Metelitsa et al. 2002). In contrast, 3F8 (murine IgG3 specific for GD2) utilizes both FcgRII and FcgRIII for ADCC (Kushner and Cheung 1992). In addition to FcR, adhesion molecules including CR3 (CD11b/Cd18) (Metelitsa et al. 2002; Kushner and Cheung 1992; Ottonello et al. 1999) and CD66b (Ottonello et al. 1999) for neutrophils,and LFA-1 (CD11a/CD18) for lymphocytes (Edwards et al. 1992), are important in modulating tumor cytotoxicity. When their expression is increased by granulocyte macrophage colony stimulating factor (GM-CSF) or IFN-g, granulocyte ADCC can be enhanced (Metelitsa et al. 2002; Kushner and Cheung 1989; Vaickus et al. 1990; Masucci et al. 1990). Similarly, IL-2 can increase lymphocyte ADCC (Munn and Cheung 1987; Sondel and Hank 1997). Furthermore, since both GM-CSF and IL-2 expand the effector cell pools, they have potential clinical benefits in tumor therapy when combined with MAb (Fig. 14.1).
Most NB cell lines are sensitive to CMC; however, some are resistant to complement because of anti-complement surface proteins, including CD55 (Cheung et al. 1988; Gorter and Meri 1999), CD59 (Gorter and Meri 1999; Cheng et al. 2000b) and CD46 (Gorter and Meri 1999). The effect of complement activation extends beyond direct tumor lysis. C3b deposited on tumor cells is rapidly cleaved by plasma protease factor I to iC3b. Through CR3 (Mac-1
Effector mechanisms of monoclonal antibodies. ADEPT antibody directed enzyme prodrug therapy; ADCC antibody-dependent cell-mediated cytotoxicity, CMC complement mediated cytotoxicity, MAb monoclonal antibody, scFv single-chain Fv fragment. (From Cheung 2004; Carter 2001).
or alphaMbeta2-integrin), and CR4 (CD11c/CD18, alphaXbeta2-integrin) receptors on leukocytes,tumor cells are opsonized (Ross et al. 1999). C3a and C5a, byproducts of complement activation, are potent mediators of inflammation (Hugli 1978) and are chemotactic for phagocytic leukocytes, drawing them to the tumor sites. C5a can also induce secondary cytokines to increase vascular permeability for both MAb and effector cells.
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