the Bing Program for Waldenstrm’s Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston
    CareStat, Newton, MA
    UCLA Medical Center, Los Angeles, CA
    Greenebaum Cancer Center, University of Maryland, Baltimore, MD
    Nevada Cancer Center, Las Vegas, NV
    Fred Hutchinson Cancer Research Center, Seattle WA
    Karolinska University Hospital, Stockholm, Sweden

    ABSTRACT

    PATIENTS AND METHODS: Sequence analysis of the entire coding region of Fc{gamma}RIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known.

    RESULTS: Variations in five codons of Fc{gamma}RIIIA were identified. Two were commonly observed (Fc{gamma}RIIIA-48 and Fc{gamma}RIIIA-158) and predicted for amino acid polymorphisms at Fc{gamma}RIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-158F/F were always Fc{gamma}RIIIA-48L/L, and patients with either Fc{gamma}RIIIA-L/R or -L/H always expressed at least one valine at Fc{gamma}RIIIA-158 (P ≤ .001). The response trend was higher for patients with Fc{gamma}RIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with Fc{gamma}RIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with Fc{gamma}RIIIA-48L/L were higher when at least one valine was present at Fc{gamma}RIIIA-158 (P = .057), thereby supporting a primary role for Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-48 and -158 polymorphisms.

    CONCLUSION: The results of these studies therefore support a predictive role for Fc{gamma}RIIIA-158 polymorphisms and responses to rituximab in WM.

    INTRODUCTION

    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 Fc{gamma}RIIIA receptor, a receptor mainly expressed on NK cells.18-20

    Polymorphisms in positions 48 and 158 of the Fc{gamma}RIIIA 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 Fc{gamma}RIIIA receptor result in expression of either leucine (L), arginine (R), or histidine (H), the first of which is linked to Fc{gamma}RIIIA-158F polymorphisms, and the latter two of which is linked to Fc{gamma}RIIIA-158V polymorphisms.21,22 However, the binding of IgG1 to Fc{gamma}RIIIA appeared to occur independent of position 48 polymorphisms in this study.21

    The contribution of Fc{gamma}RIIIA 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 Fc{gamma}RIIIA 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 Fc{gamma}RIIIA in 58 patients with WM who received rituximab, and report the association of the two most common polymorphism sites (Fc{gamma}RIIIA-48 and -158) with clinical responses.

    PATIENTS AND METHODS

    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 Fc{gamma}RIIIA 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

    Statistical Analysis

    Comparison of study parameters was performed using two-tailed Student’s t tests for continuous variables and two-tailed Fisher’s exact tests for variables categoric in nature. TTP analyses were restricted to responding patients and were assessed using Kaplan-Meier methodology with log-rank statistics for inferential comparisons. All analyses were performed using SAS (version 8; SAS Institute, Cary, NC) software and P values ≤ .05 were deemed to be statistically significant.

    RESULTS

    Diallelic single-nucleotide changes in position 526 (T->G) were also detected by sequencing, which predicted for the following amino acid polymorphisms at Fc{gamma}RIIIA-158: phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). The frequencies for these Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-48 and Fc{gamma}RIIIA-158 polymorphisms was detected. All patients with the Fc{gamma}RIIIA-158F/F polymorphism were Fc{gamma}RIIIA-48L/L, whereas patients with either the Fc{gamma}RIIIA-L/R or -L/H polymorphisms expressed at least one valine at Fc{gamma}RIIIA-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 (G->A), which did not result in an amino acid change (serine->serine). A single nucleotide change (T->A) 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/L->L/Q, whereas in another patient, an (A->T) change at nucleotide position 694 predicted for a change from asparagine (N) to tyrosine (Y) and a change in expression from N/N->N/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 Fc{gamma}RIIIA 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 Fc{gamma}RIIIA-48 or Fc{gamma}RIIIA-158 polymorphisms, did not demonstrate any significant differences (Tables 3 and 4).

    Patient Responses and Polymorphisms

    Fc{gamma}RIIIA-48 polymorphisms and rituximab response. The overall response rate for patients treated with rituximab, based on their predicted amino acid polymorphisms in Fc{gamma}RIIIA-48, were as follows: nine of 41 (22.0%) for Fc{gamma}RIIIA-48L/L; one of four (25%) for Fc{gamma}RIIIA L/R; and five of 13 (38.5%) for Fc{gamma}RIIIA L/H (Table 5). Although an increased overall response rate was observed among patients with the predicted Fc{gamma}RIIIA-48L/H versus Fc{gamma}RIIIA-48L/L and -L/R polymorphisms, these differences did not reach statistical significance.

    Fc{gamma}RIIIA-158 polymorphisms and rituximab response. An increased response rate was observed among patients with the predicted Fc{gamma}RIIIA-158V/V (four of 10; 40.0%) or -158 V/F (nine of 26; 35.0%) polymorphisms versus those patients with the Fc{gamma}RIIIA-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).

    Analysis of combined Fc{gamma}RIIIA-48 and -158 polymorphisms and rituximab response. Given that patients with the Fc{gamma}RIIIA-158F/F polymorphism always expressed Fc{gamma}RIIIA-48L/L, and those patients with either the Fc{gamma}RIIIA-L/R or -L/H polymorphisms always expressed at least one valine at Fc{gamma}RIIIA-158, we next analyzed the relationship of Fc{gamma}RIIIA-48 and -158 polymorphisms and response to rituximab. The response rates combining both polymorphisms are summarized in Table 7. Among patients possessing the Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-158. Because all patients possessing the Fc{gamma}RIIIA-48L/R or H polymorphism expressed at least one valine amino acid at Fc{gamma}RIIIA-158, no associations for response activity with the -158 F/F polymorphism could be undertaken. However, the response rate for patients with the Fc{gamma}RIIIA-48L/R or H polymorphisms was increased when compared with that of patients with the Fc{gamma}RIIIA-48L/L and -158F/F polymorphism (35.3% v 9.0%; P = .059). This effect was slightly more pronounced for patients with the Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-48L/R or H, and those with the Fc{gamma}RIIIA-48 polymorphism who expressed at least one valine at position 158.

    With a median follow-up of 13 months, the median TTP for all patients when grouped according to their Fc{gamma}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 Fc{gamma}RIIIA-48 and -158 polymorphisms (Table 8).

    DISCUSSION

    In these studies, we sequenced all coding regions of the Fc{gamma}RIIIA 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 Fc{gamma}RIIIA receptor, one of which predicted for a silent amino acid change (Ser->Ser) 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 (Fc{gamma}RIIIA-48 and Fc{gamma}RIIIA-158), both of which have been described previously. The genotype distributions in this study for both the Fc{gamma}RIIIA-48 and Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-48 and Fc{gamma}RIIIA-158 genotypes. All patients with the Fc{gamma}RIIIA-158F/F genotype were also Fc{gamma}RIIIA-48L/L, whereas all patients with either Fc{gamma}RIIIA-48L/R or -48L/H expressed at least one valine at Fc{gamma}RIIIA-158.

    In these studies, we observed a trend for higher overall response rates in WM patients receiving rituximab who were Fc{gamma}RIIIA-48L/H versus those patients with the Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-48L/L with the genotype coexpressed at Fc{gamma}RIIIA-158. Patients with the Fc{gamma}RIIIA-48L/L genotype expressing at least one valine at Fc{gamma}RIIIA-158 demonstrated a four-fold higher response rate versus those patients coexpressing Fc{gamma}RIIIA-48L/L and -158F/F. In fact, the overall response rate for patients with Fc{gamma}RIIIA-48L/L expressing at least one valine at Fc{gamma}RIIIA-158 (36.8%) was closer in line to that of patients with Fc{gamma}RIIIA-48L/R or -48L/H (35.3%), who because of linkage always express at least one valine at Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-48L/L and -158F/F versus patients who were either Fc{gamma}RIIIA-48L/L, -48L/R, or -48L/H and expressed at least one valine at Fc{gamma}RIIIA-158.

    Central to the findings in this study was the significant impact of polymorphisms at Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-158V/V versus -158F/F polymorphism. WM patients with the Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-158V/V versus -158F/F. Human IgG1 binding and cytophilic IgG1 staining by NK cells from individuals that expressed Fc{gamma}RIIIA-158V/F were intermediate between those observed from individuals with Fc{gamma}RIIIA-158V/V and -158F/F, and were influenced by the polymorphism present at Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-158 and the Fc{gamma}RIIIA-48L/H polymorphism in particular. Larger studies will be needed to clarify the contribution of the polymorphisms at Fc{gamma}RIIIA-48 and responses in patients with the Fc{gamma}RIIIA-158V/V and -158V/F genotypes.

    Although these studies, coupled with those by Cartron et al17and Weng et al,24 support a role for Fc{gamma}RIIIA 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 Fc{gamma}RIIIA 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 Fc{gamma}RIIIA 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 Fc{gamma}RIIIA-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 Fc{gamma}RIIIA-158F/F receptor to rituximab. We have initiated molecular modeling studies examining the impact of polymorphisms at -158 and -48 on Fc{gamma}RIIIA binding to rituximab that may shed additional light on the molecular mechanisms by which polymorphisms influence rituximab responses.

    Authors’ Disclosures of Potential Conflicts of Interest

    Acknowledgment

    We thank David E. Greene, PA, and John D. Sayler, PA, for generously volunteering their time and assisting in the data collection for this study.

    NOTES

    Supported by the Bing Program for Waldenstrm’s Macroglobulinemia and the Research Fund for Waldenstrm’s at the Dana-Farber Cancer Institute, the International Waldenstrm’s Macroglobulinemia Foundation, and a National Institutes of Health Career Development Award (K23CA087977-03) to S.P.T.

    Authors’ disclosures of potential conflicts of interest are found at the end of this article.

    REFERENCES

    1. Treon SP, Kelliher A, Keele B, et al: Expression of serotherapy target antigens in Waldenstrom’s macroglobulinemia: Therapeutic applications and considerations. Semin Oncol 30:243-247, 2003

    2. Byrd JC, White CA, Link B, et al: Rituximab therapy in Waldenstrom’s macroglobulinemia: Preliminary evidence of clinical activity. Ann Oncol 10:1525-1527, 1999

    3. Weber DM, Gavino M, Huh Y, et al: Phenotypic and clinical evidence supports rituximab for Waldenstrom’s macroglobulinemia. Blood 94:125a, 1999 (abstr)

    4. Foran JM, Gupta RK, Cunningham D, et al: A UK multicentre phase II study of rituximab (chimaeric anti-CD20 monoclonal antibody) in patients with follicular lymphoma, with PCR monitoring of molecular response. Br J Haematol 109:81-88, 2000

    5. Treon SP, Agus DB, Link B, et al: CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom’s macroglobulinemia. J Immunother 24:272-279, 2001

    6. Gertz MA, Rue M, Blood E, et al: Rituximab for Waldenstrom’s macroglobulinemia (E3A98): An ECOG phase II pilot study for untreated or previously treated patients. Blood 102:148a, 2003

    7. Dimopoulos MA, Zervas C, Zomas A, et al: Treatment of Waldenstrom’s macroglobulinemia with rituximab. J Clin Oncol 20:2327-2333, 2002

    8. Treon SP, Emmanouilides C, Kimby E, et al: Extended rituximab therapy in Waldenstrom’s macroglobulinemia. Ann Oncol (in press)

    9. Weber DM, Dimopoulos MA, Delasalle K, et al: Chlorodeoxyadenosine alone and in combination for previously untreated Waldenstrom’s macroglobulinemia. Semin Oncol 30:248-252, 2003

    10. Treon SP, Branagan A, Wasi P, et al: Combination therapy with rituximab and fludarabine is highly active in Waldenstrom’s macroglobulinemia. Blood 104:215a, 2004

    11. Kimby E, Geisler C, Hagberg H, et al: Rituximab as single agent and in combination with interferon-alfa-2a as treatment of untreated and first relapse follicular or other low-grade lymphomas: A randomized phase II study. Ann Oncol 13:85, 2002

    12. Hayashi T, Anderson KC, Treon SP: Rituximab induced antibody dependent cell mediated cytotoxicity (ADCC) is enhanced by thalidomide and its analogue Revimid. Blood 100:314b, 2002

    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

    14. Treon SP, Mitsiades C, Mitsiades N, et al: Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in B-cell malignancies. J Immunother 24:263-271, 2001

    15. Janakiraman N, McLaughlin P, White CA, et al: Rituximab: Correlation between effector cells and clinical activity in NHL. Blood 92:337a, 1998

    16. Gluck WL, Hurst D, Yuen A, et al: Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-Hodgkin’s lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clin Cancer Res 10:2253-2264, 2004

    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

    18. Pelz GA, Grndy HO, Lebo RV, et al: Human Fc-gamma-R, cloning, expression and identification on of the chromosomal locus of two Fc receptors for IgG. Proc Natl Acad Sci U S A 86:1013-1110, 1989

    19. Vance BA, Huizinga TWJ, Wardwell K, et al: Binding of monomeric human IgG defines an expression polymorphism of Fc-gamma-RIII on large granular lymphocyte/natural killer cells. J Immunol 151:6429-6439, 1993

    20. Wu J, Edberg JC, Redecha PB, et al: A novel polymorphism of Fc-gamma-RIIIA (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 100:1059-1070, 1997

    21. Koene HR, Kleijer M, Alga J, et al: Fc gamma-RIII{alpha}-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gamma-RIIIA, independently of the Fc gamma-RIIIA-48L/R/H phenotype. Blood 90:1109-1114, 1997

    22. de Haas M, Koene HR, Kleijer M, et al: A triallelic Fc-gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc-gamma-RIIIA. J Immunol 156:3948-3955, 1996

    23. Anolik JH, Campbell D, Felgar RE, et al: The relationship of Fc-gamma-RIIIA genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum 48:455-459, 2003

    24. Weng WK, Levy R: Two immunoglobulin G Fc receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940-3947, 2003

    25. Farag SS, Flinn IW, Modali R, et al: Fc gamma-RIIIA and Fc gamma-RIIA polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood 301:1472-1474, 2004

    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

查询更多Receptor相关信息在本站>>

《临床肿瘤学医学期刊》2005年1月第23卷第1期