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Journal of Clinical Oncology, Vol 23, No 3 (January 20), 2005: pp. 474-481 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.06.059
Polymorphisms in Fc
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors’ Disclosures of...REFERENCES |
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RIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab.
PATIENTS AND METHODS: Sequence analysis of the entire coding region of FcRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known.
RESULTS: Variations in five codons of FcRIIIA were identified. Two were commonly observed (FcRIIIA-48 and FcRIIIA-158) and predicted for amino acid polymorphisms at FcRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcRIIIA-158F/F were always FcRIIIA-48L/L, and patients with either FcRIIIA-L/R or -L/H always expressed at least one valine at FcRIIIA-158 (P 
.001). The response trend was higher for patients with FcRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcRIIIA-48L/L were higher when at least one valine was present at FcRIIIA-158 (P = .057), thereby supporting a primary role for FcRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcRIIIA-48 and -158 polymorphisms.
CONCLUSION: The results of these studies therefore support a predictive role for FcRIIIA-158 polymorphisms and responses to rituximab in WM.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors’ Disclosures of...REFERENCES |
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50% decline in serum IgM) have been observed in 20% to 30% of patients.2-6 Higher response rates (40% to 50%) have been reported with the use of extended rituximab therapy (ie, eight infusions at 375 mg/m2/wk delivered at weeks 1 to 4 and 12 to 16).7,8 Studies combining rituximab with chemotherapy or with immunomodulators have also shown encouraging findings.9-12 In view of the above studies, the Consensus Panel III of the Second International Workshop charged with making treatment recommendations for WM recommended the use of rituximab in primary as well as salvage therapy of WM.13
With the increased use of rituximab in the treatment of WM, there has been growing interest in understanding what patient-related differences might account for the heterogeneous responses observed in WM, particularly because CD20 is widely expressed in WM, and surviving rituximab-coated tumor cells may be found in WM patients many months after antibody therapy.1,14 Increasing evidence has pointed to both quantitative and qualitative differences in natural killer (NK) cell function to explain rituximab clinical activity. Higher circulating NK cell levels and responses to rituximab have been reported in patients with low-grade non-Hodgkin’s lymphoma (NHL), suggesting that antibody-dependent cell-mediated cytotoxicity (ADCC) enacted by NK cells may be a primary mechanism by which rituximab functions.15,16 Moreover, as the recent studies by Cartron et al17 suggest, responses to rituximab may depend on polymorphisms present in the FcRIIIA receptor, a receptor mainly expressed on NK cells.18-20
Polymorphisms in positions 48 and 158 of the FcRIIIA receptor expression have been reported to influence human IgG1 binding and ADCC.19-22 Polymorphisms at position 158 result in either valine (V) or phenylalanine (F) expression, the former of which is associated with increased depletion of peripheral-blood B-cells23 and response to rituximab in patients with follicular NHL,17,24 but not chronic lymphocytic leukemia. 25 At position 48, polymorphisms of the FcRIIIA receptor result in expression of either leucine (L), arginine (R), or histidine (H), the first of which is linked to FcRIIIA-158F polymorphisms, and the latter two of which is linked to FcRIIIA-158V polymorphisms.21,22 However, the binding of IgG1 to FcRIIIA appeared to occur independent of position 48 polymorphisms in this study.21
The contribution of FcRIIIA receptor polymorphisms at position 158, as well as at other positions, in response to rituximab has not been reported for WM. WM may be a particularly relevant disease model for gaining understanding of the role of FcRIIIA receptor polymorphisms to rituximab response. Unlike other lymphomas, WM is uncommonly associated with adenopathy (< 20% of patient cases) and is centered in the bone marrow, where monoclonal antibodies are more readily able to bind and saturate tumor cells. This eliminates the penetration of antibody into bulky disease as a variable for response to rituximab. In this study, we performed sequencing for the entire DNA coding region of FcRIIIA in 58 patients with WM who received rituximab, and report the association of the two most common polymorphism sites (FcRIIIA-48 and -158) with clinical responses.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors’ Disclosures of...REFERENCES |
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Response Assessment
Complete response (CR) was defined as having resolution of all symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly. Patients achieving a partial response (PR) were defined as achieving a 50% reduction in serum IgM levels. No patients achieved a CR; hence, the overall response rate reflected only PR patients. The median time to disease progression (TTP) and progression-free survival were determined for all patients and for responders in each polymorphism group, respectively.
Analysis of FcRIIIA Polymorphisms
DNA was extracted from peripheral-blood leukocytes using a kit (Qiagen, Valencia, CA). Sequences for the primers used in these studies are listed in Table 1. Exons 1 (primers 1sF and 1nR) and 2 (primers 2sF and 2nR) were each amplified as single polymerase chain reaction (PCR) amplicons; exons 3 and 4 were each amplified in two overlapping amplicons (primer 3nF with 3sR and primer 3sF with 3nR for exon 3; primer 4nF with 4sR and primer 4sF with 4nR for exon 4); and the coding region plus some of the 3' untranslated region of exon 5 were amplified in a single amplicon using seminested primers (primer 4sF with 5sR for the first round, followed by primer 5nF with 5sR for the second round). The components of the 10-µL PCR reaction were 20 mmol/L Tris-HCl (pH8.4); 50 mmol/L KCl; 1.5 mmol/L MgCl2; 0.1 mmol/L in each of deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate, and thymidine triphosphate; 0.1 µmol/L of each primer; 5 ng/µL of genomic DNA (or a 1:100 dilution of the first round exon 5 PCR for the second round reaction); and 0.05 U/µL Taq polymerase (Taq Platinum, GIBCO BRL, Gaithersburg, MD). The thermocycling conditions were 94°C for 4 minutes, followed by 11 cycles, each with a denaturing step at 94°C for 30 seconds and an extension step at 72°C for 20 seconds, and with a 20-second annealing step that decreased 1°C/cycle, beginning at 60°C in the first cycle and decreasing to 50°C in the 11th cycle; the 11th cycle was then repeated 25 times. A 6-minute incubation at 72°C followed by a 4°C soak completed the program. Each strand of each PCR product was sequenced using dye primer chemistry (Applied Biosystems Inc, Foster City, CA). The first predicted amino acid of the extracellular domain 1 was designated as amino acid 1, and the first nucleotide position of the start codon was designated as nucleotide position 1. Others have designated the first amino acid of the signal sequence as the first amino acid.20
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.05 were deemed to be statistically significant. |
RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors’ Disclosures of...REFERENCES |
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RIIIA Sequencing and PolymorphismsRIIIA was accomplished for all 58 patients and revealed variations in five codons (Fig 1), two of which were commonly observed (FcRIIIA-48 and FcRIIIA-158) and have been described previously.21,22 Two distinct nucleotide changes at position 197 within the third exon (T
G, resulting in arginine; TA, resulting in histidine) were detected, which predicted for the following amino acid polymorphisms at FcRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). The frequencies of these FcRIIIA-48 polymorphisms for the 58 patients were as follows: L/L, 70.7%; L/H, 22.4%; and L/R, 6.9%.
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G) were also detected by sequencing, which predicted for the following amino acid polymorphisms at FcRIIIA-158: phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). The frequencies for these FcRIIIA-158 polymorphisms in the 58 patients were as follows: F/F, 37.9%; F/V, 44.8%; and V/V, 17.2%. A clear linkage between the FcRIIIA-48 and FcRIIIA-158 polymorphisms was detected. All patients with the FcRIIIA-158F/F polymorphism were FcRIIIA-48L/L, whereas patients with either the FcRIIIA-L/R or -L/H polymorphisms expressed at least one valine at FcRIIIA-158 (P = .059). Variations at nucleotide positions 32, 216, and 694 were also detected. Six of the 58 patients (10.3%) demonstrated a single nucleotide change at position 216 (GA), which did not result in an amino acid change (serineserine). A single nucleotide change (TA) at position 32 (in the signal peptide) was detected in one patient, which predicted for an amino acid change from leucine to glutamine (Q) resulting in a change in expression from L/LL/Q, whereas in another patient, an (AT) change at nucleotide position 694 predicted for a change from asparagine (N) to tyrosine (Y) and a change in expression from N/NN/Y at amino acid 214.
Patient Characteristics and Polymorphisms
Given that variations in the signal peptide and at amino acid 214 were found in only two of the 58 patients, and given that no amino acid change was predicted at position 54 from the single nucleotide substitution at that locus, no additional analysis was undertaken for these variations in FcRIIIA genomic expression. Analysis of age, male-to-female ratio, prior number of treatments, pretherapy serum IgM levels, hematocrit, and platelet count, as well as the number of rituximab infusions received for patients with any of the FcRIIIA-48 or FcRIIIA-158 polymorphisms, did not demonstrate any significant differences (Tables 3 and 4).
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RIIIA-48 polymorphisms and rituximab response.
The overall response rate for patients treated with rituximab, based on their predicted amino acid polymorphisms in FcRIIIA-48, were as follows: nine of 41 (22.0%) for FcRIIIA-48L/L; one of four (25%) for FcRIIIA L/R; and five of 13 (38.5%) for FcRIIIA L/H (Table 5). Although an increased overall response rate was observed among patients with the predicted FcRIIIA-48L/H versus FcRIIIA-48L/L and -L/R polymorphisms, these differences did not reach statistical significance.
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RIIIA-158 polymorphisms and rituximab response.
An increased response rate was observed among patients with the predicted FcRIIIA-158V/V (four of 10; 40.0%) or -158 V/F (nine of 26; 35.0%) polymorphisms versus those patients with the FcRIIIA-158F/F (two of 22; 9.0%) polymorphism (V/V v F/F, P = .059; V/F v F/F, P = .045; V/V and V/F v F/F, P = .03; Table 6).
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RIIIA-48 and -158 polymorphisms and rituximab response.
Given that patients with the FcRIIIA-158F/F polymorphism always expressed FcRIIIA-48L/L, and those patients with either the FcRIIIA-L/R or -L/H polymorphisms always expressed at least one valine at FcRIIIA-158, we next analyzed the relationship of FcRIIIA-48 and -158 polymorphisms and response to rituximab. The response rates combining both polymorphisms are summarized in Table 7. Among patients possessing the FcRIIIA-48L/L polymorphism, an increased response rate (36.8 v 9.0%; P = .057) was observed in patients predicted to be carrying at least one valine (V/V or V/F) versus those predicted to be expressing F/F at FcRIIIA-158. Because all patients possessing the FcRIIIA-48L/R or H polymorphism expressed at least one valine amino acid at FcRIIIA-158, no associations for response activity with the -158 F/F polymorphism could be undertaken. However, the response rate for patients with the FcRIIIA-48L/R or H polymorphisms was increased when compared with that of patients with the FcRIIIA-48L/L and -158F/F polymorphism (35.3% v 9.0%; P = .059). This effect was slightly more pronounced for patients with the FcRIIIA-48L/H polymorphism (38.5% v 9.0%; P = .075). No significant difference in response rate (35.3% v 36.8%) was found among patients who possessed FcRIIIA-48L/R or H, and those with the FcRIIIA-48 polymorphism who expressed at least one valine at position 158.
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RIIIA-48 and -158 polymorphisms was not significantly different (Table 8). Similarly, no significant difference in the median progression-free survival was observed when responding patients were grouped by their FcRIIIA-48 and -158 polymorphisms (Table 8).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors’ Disclosures of...REFERENCES |
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RIIIA receptor to rituximab responses.15-17,24
In these studies, we sequenced all coding regions of the FcRIIIA receptor from a series of patients with WM to first define potential polymorphisms in this receptor, and then correlated these findings to their response to rituximab. We observed single nucleotide variations in five codons of the FcRIIIA receptor, one of which predicted for a silent amino acid change (SerSer) at position 54, and four of which predicted for changes in the signal peptide, and in amino acids 48, 158, and 214. Given that variations in positions were only observed in one patient for each, we focused our analysis on the two most commonly observed polymorphisms (FcRIIIA-48 and FcRIIIA-158), both of which have been described previously. The genotype distributions in this study for both the FcRIIIA-48 and FcRIIIA-158 polymorphisms were in agreement with those previously reported.17,22,24 Consistent with the findings of Koene et al,21 we also observed a clear-cut linkage of the FcRIIIA-48 and FcRIIIA-158 genotypes. All patients with the FcRIIIA-158F/F genotype were also FcRIIIA-48L/L, whereas all patients with either FcRIIIA-48L/R or -48L/H expressed at least one valine at FcRIIIA-158.
In these studies, we observed a trend for higher overall response rates in WM patients receiving rituximab who were FcRIIIA-48L/H versus those patients with the FcRIIIA-48L/L or -48L/R genotype. Larger studies will be needed, however, to validate these differences statistically. The observed increases in clinical activity for rituximab in WM patients with FcRIIIA-L/H is consistent with the work of de Haas et al,22 who reported increased human IgG1 binding on NK cells expressing this genotype. However, as suggested by these studies, there appears to be a direct dependence for rituximab activity in patients with FcRIIIA-48L/L with the genotype coexpressed at FcRIIIA-158. Patients with the FcRIIIA-48L/L genotype expressing at least one valine at FcRIIIA-158 demonstrated a four-fold higher response rate versus those patients coexpressing FcRIIIA-48L/L and -158F/F. In fact, the overall response rate for patients with FcRIIIA-48L/L expressing at least one valine at FcRIIIA-158 (36.8%) was closer in line to that of patients with FcRIIIA-48L/R or -48L/H (35.3%), who because of linkage always express at least one valine at FcRIIIA-158. These observations are consistent with those reported by Koene et al,21 who demonstrated lower cell surface binding of human IgG1 and demonstration of cytophilic IgG staining in NK cells taken from individuals who were FcRIIIA-48L/L and -158F/F versus patients who were either FcRIIIA-48L/L, -48L/R, or -48L/H and expressed at least one valine at FcRIIIA-158.
Central to the findings in this study was the significant impact of polymorphisms at FcRIIIA-158 and responses to rituximab in WM patients. A better than a four-fold higher response rate (40% v 9.0%) was observed in patients with FcRIIIA-158V/V versus -158F/F polymorphism. WM patients with the FcRIIIA-158V/F genotype, who accounted for 44.8% of the patients in this study, demonstrated response characteristics that were more closely aligned with those of patients with FcRIIIA-158V/V versus -158F/F (Table 6). The results of these studies are consistent with previous reports demonstrating increased cell surface human IgG1 binding, cytophilic IgG1 staining, and evidence of ADCC activity by NK cells from individuals expressing FcRIIIA-158V/V versus -158F/F. Human IgG1 binding and cytophilic IgG1 staining by NK cells from individuals that expressed FcRIIIA-158V/F were intermediate between those observed from individuals with FcRIIIA-158V/V and -158F/F, and were influenced by the polymorphism present at FcRIIIA-48, as shown by Koene et al.21 We also observed a trend for a higher overall response rate among patients expressing at least one valine at FcRIIIA-158 and the FcRIIIA-48L/H polymorphism in particular. Larger studies will be needed to clarify the contribution of the polymorphisms at FcRIIIA-48 and responses in patients with the FcRIIIA-158V/V and -158V/F genotypes.
Although these studies, coupled with those by Cartron et al17and Weng et al,24 support a role for FcRIIIA polymorphisms in predicting responses to rituximab in patients with certain lymphomas, such insight may not be applicable to all B-cell malignancies, as suggested in study of chronic lymphocytic leukemia patients receiving rituximab by Farag et al.25 However, for certain B-cell malignancies, advance knowledge of a patient’s FcRIIIA polymorphism status may facilitate a clinician’s decision to employ rituximab monotherapy versus chemotherapy alone or combined rituximab and chemotherapy. Larger studies to validate such algorithms are planned. Moreover, as suggested by the work of Shields et al,26 monoclonal antibodies could be modified by specific amino acid substitutions to enhance FcRIIIA binding and NK cell–mediated ADCC activity in patients with either the -158F/F or -158V/V polymorphisms, thereby potentially making such antibodies more broadly successful. Interestingly, most of these substitutions involved a less bulky amino acid, and particularly benefited interactions with FcRIIIA-158F/F over the -158V/V receptor. Given that phenylalanine is considerably bulkier than valine, steric hindrance may prevent ideal binding of NK cells bearing the FcRIIIA-158F/F receptor to rituximab. We have initiated molecular modeling studies examining the impact of polymorphisms at -158 and -48 on FcRIIIA binding to rituximab that may shed additional light on the molecular mechanisms by which polymorphisms influence rituximab responses.
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Authors’ Disclosures of Potential Conflicts of Interest |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors’ Disclosures of...REFERENCES |
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Acknowledgment |
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NOTES |
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Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAuthors’ Disclosures of...REFERENCES |
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13. Gertz M, Anagnostopoulos A, Anderson KC, et al: Treatment Recommendations in Waldenstrom’s macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol 30:121-126, 2003[CrossRef][Medline]
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17. Cartron G, Dacheux L, Salles G, et al: Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor Fc-gamma-RIIIA gene. Blood 99:754-758, 2002
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26. Shields RL, Namenuk AK, Hong K, et al: High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to Fc gamma R. J Biol Chem 276:6591-6604, 2001
Submitted June 7, 2004; accepted October 15, 2004.
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A. Vijay and M. A. Gertz Waldenstrom macroglobulinemia Blood, June 15, 2007; 109(12): 5096 - 5103. [Abstract] [Full Text] [PDF]
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A. S. Haider, M. A. Lowes, H. Gardner, R. Bandaru, K. Darabi, F. Chamian, T. Kikuchi, P. Gilleaudeau, M. S. Whalen, I. Cardinale, et al. Novel Insight into the Agonistic Mechanism of Alefacept In Vivo: Differentially Expressed Genes May Serve as Biomarkers of Response in Psoriasis Patients J. Immunol., June 1, 2007; 178(11): 7442 - 7449. [Abstract] [Full Text] [PDF]
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S. P. Treon, Z. R. Hunter, J. Matous, R. M. Joyce, B. Mannion, R. Advani, D. Cook, J. Songer, J. Hill, B. R. Kaden, et al. Multicenter Clinical Trial of Bortezomib in Relapsed/Refractory Waldenstrom's Macroglobulinemia: Results of WMCTG Trial 03-248 Clin. Cancer Res., June 1, 2007; 13(11): 3320 - 3325. [Abstract] [Full Text] [PDF]
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D. H. Kim, H. D. Jung, J. G. Kim, J.-J. Lee, D.-H. Yang, Y. H. Park, Y. R. Do, H. J. Shin, M. K. Kim, M. S. Hyun, et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma Blood, October 15, 2006; 108(8): 2720 - 2725. [Abstract] [Full Text] [PDF]
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S. P. Treon, M. A. Gertz, M. Dimopoulos, A. Anagnostopoulos, J. Blade, A. R. Branagan, R. Garcia-Sanz, S. Johnson, E. Kimby, V. LeBlond, et al. Update on treatment recommendations from the Third International Workshop on Waldenstrom's Macroglobulinemia Blood, May 1, 2006; 107(9): 3442 - 3446. [Abstract] [Full Text] [PDF]
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P. V. Beum, A. D. Kennedy, M. E. Williams, M. A. Lindorfer, and R. P. Taylor The Shaving Reaction: Rituximab/CD20 Complexes Are Removed from Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Cells by THP-1 Monocytes J. Immunol., February 15, 2006; 176(4): 2600 - 2609. [Abstract] [Full Text] [PDF]
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RIIIA (CD16) Receptor Expression Are Associated With Clinical Response to Rituximab in Waldenström’s Macroglobulinemia
