Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa
Open accessAbstract
Purpose: Recent studies have revealed that fucosylated therapeutic IgG1s need high concentrations to compensate for FcγRIIIa-competitive inhibition of antibody-dependent cellular cytotoxicity (ADCC) by endogenous human plasma IgG. Here, we investigated whether ADCC of nonfucosylated therapeutic IgG1 is also influenced by plasma IgG in the same way as fucosylated IgG1s. Experimental Design: Ex vivo ADCC upon CD20+ human B cells was induced by incubation of human whole blood with nonfucosylated and/or fucosylated anti-CD20 IgG1s rituximab, and quantified by measuring the remaining CD19+ human B cells using flow cytometry. Results: Nonfucosylated anti-CD20 showed markedly higher (over 100-fold based on EC50) ex vivo B-cell depletion activity than its fucosylated counterpart in the presence of plasma IgG. The efficacy of fucosylated anti-CD20 was greatly diminished in plasma, resulting in the need for a high concentration (over 1.0 μg/mL) to achieve saturated efficacy. In contrast, nonfucosylated anti-CD20 reached saturated ADCC at lower concentrations (0.01-0.1 μg/mL) with much higher efficacy than fucosylated anti-CD20 in all nine donors through improved FcγRIIIa binding. Noteworthy, the high efficacy of nonfucosylated anti-CD20 was inhibited by addition of fucosylated anti-CD20. Thus, the efficacy of a 1:9 mixture (10 μg/mL) of nonfucosylated and fucosylated anti-CD20s was inferior to that of a 1,000-fold dilution (0.01 μg/mL) of nonfucosylated anti-CD20 alone. Conclusions: Our data showed that nonfucosylated IgG1, not including fucosylated counterparts, can evade the inhibitory effect of plasma IgG on ADCC through its high FcγRIIIa binding. Hence, nonfucosylated IgG1 exhibits strong therapeutic potential through dramatically enhanced ADCC at low doses in humans in vivo.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
This increased affinity allows better therapeutic activity of Mabs used in cancer therapy, by triggering the antibody-dependent-cell-mediated cytotoxicity (ADCC) pathway.
“This increased affinity allows better therapeutic activity of Mabs used in cancer therapy, by triggering the antibody-dependent-cell-mediated cytotoxicity (ADCC) pathway (Niwa et al., 2005;Iida et al., 2006;Chung et al., 2012).”
From Therapeutic glycoprotein production in mammalian cells (2017) · cites this paper as Iida et al., 2006
The Introduction (page not available) links higher FcγRIIIa affinity with a superior clinical response to rituximab, and the Discussion reports that improved FcγRIIIa binding enhances ADCC. However, this paper’s test of nonfucosylated antibodies used a human ex vivo model; it supports improved ADCC and therapeutic potential, not established better therapeutic activity in cancer patients. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
No citation lists for this paper
No citation lists for this paper yet — checked again daily.
References 51 · Cited by 206
Research works printed but not linked: 45
- Carter P. Improving the efficacy of antibody-based cancer therapies. Nat Rev Cancer 2001;1:118 ^29.
- Glennie MJ, van de Winkel JGJ. Renaissance of can- cer therapeutic antibodies. Drug Discov Today 2003;8:503 ^10.
- Smith MR. Rituximab (monoclonal anti-CD20 anti- body): mechanisms of action and resistance. Onco- gene 2003;22:7359 ^68.
- Forero A, Lobuglio AF. History of antibody therapy for non-Hodgkin's lymphoma. Semin Oncol 2003; 30:1 ^5.
- Grillo-Lopez AJ. Rituximab (Rituxan/MabThera): the first decade (1993-2003). Expert Rev AnticancerTher 2003;3:767 ^9.
- Vogel CL, Franco SX. Clinical experience with trastu- zumab (Herceptin). Breast J 2003;9:452 ^62.
- Cartron G, Dacheux L, Salles G, et al.Therapeutic ac- tivity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgRIIIa gene. Blood 2002;99:754 ^8.
- Dall'Ozzo S,Tartas S, Paintaud G, et al. Rituximab-de- pendent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res 2004;64:4664 ^9.
- Anolik JH, Campbell D, Felgar RE, et al. The relation- ship of FcgRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus eryth- ematosus. Arthritis Rheum 2003;48:455 ^9.
- Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict re- sponse to rituximab in patients with follicular lympho- ma. J Clin Oncol 2003;21:3940 ^7.
- Gennari R, Menard S, Fagnoni F, et al. Pilot study of the mechanism of action of preoperative trastuzu- mab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 2004;10: 5650 ^5.
- Shields RL, Lai J, Keck R, et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves bind- ing to human FcgRIII and antibody-dependent cellular toxicity. J Biol Chem 2002;277:26733 ^40.
- Yamane-Ohnuki N, Kinoshita S, Inoue-Urakubo M, et al. Establishment of FUT8 knockout Chinese ham- ster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol Bioeng 2004;87:614 ^22.
- Mori K, Kuni-Kamochi R, Yamane-Ohnuki N, et al. Engineering Chinese hamster ovary cells to maximize effector function of produced antibodies using FUT8 siRNA. Biotechnol Bioeng 2004;88:901 ^8.
- Berinstein NL, Grillo-Lopez AJ,White CA, et al. As- sociation of serum rituximab (IDEC-C2B8) concentra- tion and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lym- phoma. Ann Oncol 1998;9:995 ^1001.
- Goldenberg MM. Trastuzumab, a recombinant DNA- derived humanized monoclonal antibody, a novel agent for the treatment of metastatic breast cancer. ClinTher 1999;21:309 ^18.
- Sliwkowski MX, Lofgren JA, Lewis GD, HotalingTE, Fendly BM, Fox JA. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol 1999;26:60 ^70.
- Lewis GD, Figari L, Fendly B, et al. Differential responses of human tumor cell lines to anti- p185HER2 monoclonal antibodies. Cancer Immunol Immunother 1993;37:255 ^63.
- VugmeysterY, Howell K. Rituximab-mediated deple- tion of cynomolgus monkey B cells in vitro in different matrices: possible inhibitory effect of IgG. Int Immuno- pharmacol 2004;4:1117 ^24.
- Preithner S, Elm S, Lippold S, et al. High concentra- tions of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immuno- globulin G. Mol Immunol 2006;43:1183 ^93. Epub 2005 August 15.
- Mizuochi T, Taniguchi T, Shimizu A, Kobata A. Structural and numerical variations of the carbohy- drate moiety of immunoglobulin G. J Immunol 1982;129:2016 ^20.
- Harada H, Kamei M, Tokumoto Y, et al. Systematic fractionation of oligosaccharides of human immuno- globulin G by serial affinity chromatography on immobilized lectin columns. Anal Biochem 1987; 164:374 ^81.
- Kamoda S, Nomura C, Kinoshita M, et al. Profiling analysis of oligosaccharides in antibody pharmaceuti- cals by capillary electrophoresis. J Chromatogr A 2004;1050:211 ^6.
- Niwa R, Hatanaka S, Shoji-Hosaka E, et al. Enhance- ment of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 is independent of FcgRIIIa func- tional polymorphism. Clin Cancer Res 2004;10: 6248 ^55.
- Okazaki A, Shoji-Hosaka E, Nakamura K, et al. Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate be- tween IgG1 and FcgRIIIa. J Mol Biol 2004;336: 1239 ^49.
- Niwa R, Sakurada M, Kobayashi Y, et al. Enhanced natural killer cell binding and activation by low-fucose IgG1 antibody results in potent antibody-dependent cellular cytotoxicity induction at lower antigen density. Clin Cancer Res 2005;11:2327 ^36.
- Urlaub G, Mitchell PJ, Kas E, et al. Effect of g rays at the dihydrofolate reductase locus: deletions and inver- sions. Somat Cell Mol Genet 1986;12:555 ^66.
- Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185HER2 antibody for human cancer ther- apy. Proc Natl Acad Sci U S A 1992;89:4285 ^9.
- Nakamura K,TanakaY, Fujino I, Hirayama N, Shitara K, Hanai N. Dissection and optimization of immune effector functions of humanized anti-ganglioside GM2 monoclonal antibody. Mol Immunol 2000;37: 1035 ^46.
- KandaY,Yamane-Ohnuki N, Sakai N, et al. Compari- son of cell lines for stable production of fucose- negative antibodies antibodies with enhanced ADCC. Biotechnol Bioeng. In press 2006.
- Vugmeyster Y, Howell K, Bakshl A, Flores C, Canova-Davis E. Effect of anti-CD20 monoclonal anti- body, Rituxan, on cynomolgus monkey and human B cells in a whole blood matrix. Cytometry A 2003;52: 101 ^9.
- Wahl AF, Klussman K,Thompson JD, et al. The anti- CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin's dis- ease. Cancer Res 2002;62:3736 ^42.
- Tai YT, Catley LP, Mitsiades CS, et al. Mechanisms by which SGN-40, a humanized anti-CD40 anti- body, induces cytotoxicity in human multiple myelo- ma cells: clinical implications. Cancer Res 2004;64: 2846 ^52.
- Umana P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE. Engineered glycoforms of an antineuroblas- toma IgG1with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol 1999;17:176 ^80.
- Presta LG. Engineering antibodies for therapy. Curr Pharm Biotechnol 2002;3:237 ^56.
- Shields RL, Namenuk AK, Hong K, et al. High reso- lution mapping of the binding site on human IgG1 for FcgRI, FcgRII, FcgRIII, and FcRn and design of IgG1 variants with improved binding to the FcgR. J Biol Chem 2001;276:6591 ^604.
- van Ojika HH, Bevaart L, Dahle CE, et al. CpG-A and B oligodeoxynucleotides enhance the efficacy of anti- body therapy by activating different effector cell pop- ulation. Cancer Res 2003;63:5595 ^600.
- Jahrsdorfer B, Weiner GJ. Immunostimulatory CpG oligodeoxynucleotides and antibody therapy of can- cer. Semin Oncol 2003;30:476 ^82.
- Friedberg JW, Neuberg D, Gribben JG, et al. Com- bination immunotherapy with rituximab and interleu- kin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma. Br J Haematol 2002;117: 828 ^34.
- Stockmeyer B, Elsasser D, Dechant M, et al. Mech- anisms of G-CSF-or GM-CSF-stimulated tumor cell killing by Fc receptor-directed bispecific antibodies. J Immunol Methods 2001;248:103 ^11.
- Niwa R, Natsume A, Uehara A, et al. IgG subclass- independent improvement of antibody-dependent cellular cytotoxicity by fucose removal from Asn 297 - linked oligosaccharides. J Immunol Methods 2005; 306:151 ^60.
- Niwa R, Shoji-Hosaka E, Sakurada M, et al. Defuco- sylated anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T cell leukemia and lymphoma. Cancer Res 2004;64:2127 ^33.
- Voso MT, Pantel G, Rutella S, et al. Rituximab reduces the number of peripheral blood B-cells in vitro mainly by effector cell-mediated mechanisms. Haematologica 2002;87:918 ^25.
- Manches O, Lui G, Chaperot L, et al. In vitro mech- anisms of action of rituximab on primary non-Hodgkin lymphomas. Blood 2003;101:949 ^54.
- Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435 ^45.
- Authors
- Iida, S., Misaka, H., Inoue, M., Shibata, M., Nakano, R., Yamane-Ohnuki, N., Wakitani, M., Yano, K., Shitara, K., & Satoh, M.
- Affiliations
- Authors' Affiliation: Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Machida-shi, Tokyo, Japan
- Venue
- Clinical Cancer Research
- Published
- 2006-05-01
- Volume
- 12
- Issue
- 9
- Pages
- 2879-2887
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2156750419
- Cited by
- 206
- References
- 51
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 5 · 2021: 16 · 2020: 8 · 2019: 6 · 2018: 20 · 2017: 14 · 2016: 13 · 2015: 13 · 2014: 10 · 2013: 12 · 2012: 14
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Keywords
- antibody-dependent cellular cytotoxicity, FcγRIIIa binding, fucosylation, rituximab, anti-CD20 monoclonal antibody, B-cell depletion, CD20
- MeSH terms
- Rituximab, Animals, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Antineoplastic Agents, B-Lymphocytes, Blood Donors, Fucose, Cricetinae, Humans, Immunoglobulin G, Lymphocyte Depletion, CHO Cells, Receptors, IgG, Erb-b2 Receptor Tyrosine Kinases, Antigens, CD20, Mice, Antibodies, Monoclonal, Murine-Derived
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
