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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2220.
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IMMUNOBIOLOGY
Comment on Hatjiharissi et al, page 2561
Fc RIIIa role in rituximab efficacy
Julie M. Roda, and
John C. Byrd
THE OHIO STATE UNIVERSITY
In this issue of Blood, Hatjiharissi and colleagues demonstrate that variability in NK-cell activity among individuals expressing different Fc RIIIa polymorphisms may result from variability in levels of receptor expression and not strictly from differences in receptor affinity, as was previously thought. These results have important implications for our ability to predict patient response to antibody-based therapeutics, as well as for our ability to design strategies to improve these drugs.
The gene encoding FcRIIIa (CD16), an activating Fc receptor expressed primarily on natural killer (NK) cells, has 2 allelic single-nucleotide polymorphic (SNP) variants, valine (V) or phenylalanine (F), at position 158. The 158V SNP exhibits a higher binding affinity for human immunoglobulin G1 (IgG1) than the 158F SNP, and higher levels of antibody-dependent cellular cytotoxicity (ADCC) have been observed in NK cells from homozygous V/V individuals. In 2000, Clynes et al1 reported that mice genetically deficient in FcR had greatly diminished response to therapy with rituximab, an anti-CD20 monoclonal antibody used in the treatment of B-cell malignancies. Other xenograft NK-cell depletion studies2,3 have confirmed these findings.
As a consequence of this ongoing research, it has gradually become accepted that Fc- receptor–mediated immune mechanisms contribute substantially to the mechanisms of action of antitumor antibodies. Consequently, investigators began to examine the relationship between the specific FcRIIIa genotype and clinical outcome in patients receiving antitumor antibodies. Cartron et al4 demonstrated that non-Hodgkin lymphoma (NHL) patients carrying the 158V/V genotype had significantly improved objective response rates as compared with patients carrying at least one 158F allele, further supporting the role of FcR-mediated effector functions in general, and NK cells in particular, in the antitumor effects of rituximab in NHL.
The association between FcRIIIa genotype and clinical outcome generally has been attributed to differences in IgG binding affinity. However, in the current report, Hatjiharissi and colleagues quantitatively measured the number of FcRIIIa molecules expressed on the NK-cell surface in donors of different FcRIIIa genotypes. These investigators found that NK cells from individuals carrying at least one 158V allele had significantly higher cell-surface expression of FcRIIIa than individuals possessing two 158F alleles. NK-cell antibody–dependent cellular cytotoxicity (ADCC) against rituximab-coated target cells also correlated with FcRIIIa expression levels, with the NK-cell donors expressing the highest number of CD16 molecules per NK cell having the highest ADCC activity. In confirmation of previous reports, the authors use a competition assay to demonstrate that NK cells from 158V/V donors bind rituximab more strongly than 158V/F or 158F/F NK cells, an effect which is independent of the number of receptors expressed on the cell surface. Although the study is somewhat limited by the low number of donors examined, it is likely that both mechanisms contribute to the higher clinical benefit rates observed in 158V/V patients receiving rituximab. Further mechanistic studies of context-identical genotyped cells will be required to determine "where the beef" is, relative to rituximab efficacy and the importance of FcRIIIa affinity versus FcRIIIa-receptor expression on NK cells.
The importance of the findings put forth by Hatjiharissi and colleagues are substantial, and relate to both alternative effector-cell contribution to antibody therapy and to novel ways NK-cell ADCC might be augmented. Clynes et al1 have shown that genetic deletion of FcRIIb, an inhibitory Fc receptor expressed on monocytes, significantly improves the antitumor response to rituximab. Other reports have also demonstrated that the effects of anti-CD20 mAbs are substantially reduced in mice depleted of monocytes.5 These reports suggest that monocytes/macrophages might also contribute to the clearance of B cells following rituximab administration. Consistent with this hypothesis, a genetic polymorphism in FcRIIa (histidine/arginine at position 131), an activating receptor expressed on monocytes, has been correlated with clinical response to rituximab. However, unlike the case for the FcRIIIa 158 dimorphism, the FcRIIa allotypes exhibit similar binding activity to rituximab, and therefore it is currently unclear how the dimorphism influences clinical response to rituximab. It will therefore be important to conduct similar studies investigating the relationship between the FcRIIa genotype and receptor-expression levels. Such a correlation, if found, may explain the association of the 131H/H polymorphism with greater response to rituximab.
With respect to targeting NK cells, these findings suggest that the coadministration of immune modulatory adjuvants known to up-regulate FcRIIIa expression may enhance rituximab-specific NK-cell activity in NHL patients, thereby improving clinical outcome. These studies thereby strongly support the use of NK-cell–activating adjuvants in combination with rituximab in NHL patients.
Footnotes
Conflict-of-interest disclosure: The authors declare no competing financial interests. 
REFERENCES
- Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nature Med 2000; 6:443–446.[CrossRef][Medline]
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- Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res 2005; 11:5984–5992.[Abstract/Free Full Text]
- Zhao XB, Lapalombella R, Joshi T, et al. Targeting CD37+ lymphoid malignancies with a novel engineered small modular immunopharmaceutical. Blood Prepublished on April 17 2007, as DOI 10.1182/blood-2006-12-062927.[Abstract/Free Full Text]
- Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcRIIIa gene. Blood 2002; 99:754–758.[Abstract/Free Full Text]
- Uchida J, Hamaguchi Y, Oliver JA, et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor–dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004; 199:1659–1669.[Abstract/Free Full Text]
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Related Article in Blood Online:
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Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcRIIIa-158 V/V and V/F polymorphism
- Evdoxia Hatjiharissi, Lian Xu, Daniel Ditzel Santos, Zachary R. Hunter, Bryan T. Ciccarelli, Sigitas Verselis, Michael Modica, Yang Cao, Robert J. Manning, Xavier Leleu, Elizabeth A. Dimmock, Alexandros Kortsaris, Constantine Mitsiades, Kenneth C. Anderson, Edward A. Fox, and Steven P. Treon
Blood 2007 110: 2561-2564.
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