Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene

Abstract

Given that the Fc␥RIIIa receptor 158V allotype displays a higher affinity for human immunoglobulin G1 and increased antibody-dependent cellular cytotoxicity, the aim of this study was to determine the influence of that FCGR3A polymorphism on the therapeutic response to rituximab, an anti-CD20 humanized immunoglobulin G1 increasingly used in the treatment of non-Hodgkin lymphomas. The FCGR3A-158V/F genotype was determined in 49 patients having received rituximab for a previously untreated follicular nonHodgkin lymphoma. The clinical response and the disappearance of the BCL2-JH gene rearrangement in both peripheral blood and bone marrow were evaluated at 2 months (M2) and at 1 year (M12). The study population consisted of 20% FCGR3A-158V homozygous patients, 35% FCGR3A-158F homozygous patients, and 45% heterozygous patients (FCGR3A-158F carriers). The objective response rates at M2 and M12 were 100% and 90%, respectively, in FCGR3A-158V homozygous patients compared with 67% (P ‫؍‬ .03) and 51% (P ‫؍‬ .03), respectively, in FCGR3A-158F carriers. A disappearance of the BCL2-JH gene rearrangement in both peripheral blood and marrow was observed at M12 in 5 of 6 of homozygous IntroductionRituximab (Mabthera, Rituxan) is a chimeric anti-CD20 immunoglobulin G1 (IgG1) monoclonal antibody consisting of human ␥1 and constant regions linked to murine variable domains. 1 Over the last few years, rituximab has considerably modified the therapeutic strategy for B lymphoproliferative malignancies, particularly non-Hodgkin lymphomas (NHLs). Rituximab, alone or in combination with chemotherapy, was shown to be effective in the treatment of both low-intermediate 2-8 and high-grade NHL. 6,9 Unfortunately, 30% to 50% of patients with low-grade NHL exhibit no clinical response to rituximab. 4,5 It has been suggested that the level of CD20 expression on lymphoma cells, 2 the presence of high tumor burden at the time of treatment, 6 or low serum rituximab concentrations 2,10 may explain the lack of efficacy of rituximab in some patients. Nevertheless, the actual causes of treatment failure remain largely unknown.In vitro studies suggest that rituximab induces lymphoma cell lysis in vitro through antibody-dependent cell-mediated cytotoxicity (ADCC), 11,12 complement-dependent cytotoxicity, 11,13,14 or direct signaling leading to apoptosis. 15,16 ADCC is an important effector mechanism in the eradication of intracellular pathogens and tumor cells. It requires leukocyte receptors for the Fc portion of IgG (Fc␥R), whose function is to link the IgG-sensitized antigens to Fc␥R-bearing cytotoxic cells and to trigger the cell activation mechanisms. The role of ADCC is still controversial, 13,14 but the implication of Fc␥R in the antitumor effects of anti-CD20 antibodies against human lymphoma cell lines has been demonstrated in murine models. [17][18][19] Three classes of Fc␥R (Fc␥RI, Fc␥RII, and Fc␥RIII) and their subclasses are encoded by 8 genes in humans, all located on the long arm of chromosome 1. Some of those genes display a functi...

What lessons can be learned from γδ T cell-based cancer immunotherapy trials?

“…Efficacy of the treatment in the relapsing follicular lymphoma patients was expected to result from the enhancement of ADCC by rituximab/ BrHPP/IL-2 co-administration. Indeed, polymorphisms in the IgG Fc receptor FccRIIIa gene strongly affect the efficacy of ADCC in patients undergoing rituximab-based therapies 63 and the individual pharmacokinetics for each patient. 64 Therefore, genotyping patients and determining their cancer biomarkers prior to the use of cd cell-based protocols could provide patients with the most appropriate options.…”

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

“…Among these mechanisms, studies on rituximab and trastuzumab have suggested that ADCC is the key mechanism of action to eliminate cancer cells. 5-7 …”

4‐1BB ligand modulates direct and Rituximab‐induced NK‐cell reactivity in chronic lymphocytic leukemia

“…Multiple efforts are made to increase the efficacy of antitumor antibodies, and many strategies focus on modifications serving to increase ADCC of NK cells [5]. Evidence for the importance of the latter has been derived from animal models and analyses with lymphoma patients treated with Rituximab who displayed FcgR polymorphisms (e.g., [6][7][8]). …”