Future Directions To Improve Efficacy Of Monoclonal Therapy

Based on the findings we review in this chapter, how can we improve the clinical activity of rituximab against tumor cells? Given that ADCC activity is an important action of rituximab, several approaches have been proposed. First, higher-dose infusions of rituximab may overcome low binding affinity to rituximab, although clinical trials have not been done yet. Second, concurrent administration of cytokines or growth factors has been proposed to increase the activity of ADCC effector cells.

Based on the finding that IL-2, IL-12, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ADCC activities of effector cells (73), several trials have demonstrated improved activity of effector cells by administration of cytokines or growth factor (54,74). However, with regard to clinical response, it is difficult to make conclusions about the efficacy of this approach without further clinical trials.

Another approach is to increase the binding affinity of the Fc portion in rituximab for the Fcy receptor on effector cells. Several kinds of genetically reengineered monoclonal antibodies have been developed and are under investigation. Modification of IgG glycosylation, which is necessary for the interaction of IgG with Fc^ receptor, has been studied (43, 75, 76). Removal of fucose residues from the oligosaccharides of human IgG1, which makes a low-fucose version of rituximab, has been shown to improve binding to human Fc^RIII (up to 50-100 fold) and ADCC activity in an in vitro model (43,75). Based on the requirement of N-Glycans at Asn-297 in the Fc domain of IgG for Fc receptor-mediated effector functions, N-glycan remodeling in vitro has been shown to increase ADCC activity of rituximab 10-fold (76). These two approaches of modifying glycosylation of rituximab Fc portion are promising.

Recently, two groups reported a genetically reengineered version of rituximab to have enhanced affinity for the Fc^ receptor. Bowles et al. (77) recently developed rituximab with varying affinity for Fc receptor and for CD20 antigen using a directed evolution approach. The reengineered version of rituximab with higher affinity to CD20 antigen and Fcy receptor was more effective at modulating CD16 (Fc^RIII), activating NK cells and ADCC even in a group expressing lower affinity Fc^R.

Another approach is to use rituximab variants with re-engineered Fc portions (Macro-Genics, Inc, Rockville, MD, USA) using single amino acid substitution by screening a yeast library containing randomly mutated Fc. Weng et al. (78) reported that the rituximab variants with re-engineered Fc showed increased interaction with Fc^R on effectors and mediated ADCC more effectively than rituximab even with effectors of low-affinity genotypes of FCGR3A. Accordingly, these two types of reengineered versions of rituximab can be more effective toward CD20 (+) hematologic malignancies than rituximab, especially for patients with the FF genotype of FCGR3A-158. However, further clinical study to determine safety and clinical efficacy is strongly warranted.

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