A Critical Review of the Role of Fc Gamma Receptor Polymorphisms in the Response to Monoclonal Antibodies in Cancer

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2013 Jan 5

PMID 23286345

Citations 164

Authors

James D Mellor

Michael P Brown

Helen R Irving

John R Zalcberg

Alexander Dobrovic

Affiliations

Soon will be listed here.

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism of action of therapeutic monoclonal antibodies (mAbs) such as cetuximab, rituximab and trastuzumab. Fc gamma receptors (FcgR) on human white blood cells are an integral part of the ADCC pathway. Differential response to therapeutic mAbs has been reported to correlate with specific polymorphisms in two of these genes: FCGR2A (H131R) and FCGR3A (V158F). These polymorphisms are associated with differential affinity of the receptors for mAbs. This review critically examines the current evidence for genotyping the corresponding single nucleotide polymorphisms (SNPs) to predict response to mAbs in patients with cancer.

Citing Articles

Novel oral adjuvant to enhance cytotoxic memory like NK cell responses in HIV vaccine platform.

Alles M, Gunasena M, Isckarus C, De Silva I, Board S, Mulhern W NPJ Vaccines. 2025; 10(1):5.

PMID: 39799133 PMC: 11724931. DOI: 10.1038/s41541-024-01053-1.

Flow Cytometric Assessment of FcγRIIIa-V158F Polymorphisms and NK Cell Mediated ADCC Revealed Reduced NK Cell Functionality in Colorectal Cancer Patients.

Schiele P, Kolling S, Rosnev S, Junkuhn C, Walter A, von Einem J Cells. 2025; 14(1.

PMID: 39791733 PMC: 11720420. DOI: 10.3390/cells14010032.

Organocatalysed synthesis of -(4-oxo-2-phenyl-1,2-dihydroquinazolin-3(4)-yl)isonicotinamide: computational, electrochemical, drug-likeness and antimicrobial studies.

Mane R, Yaraguppi D, Bagewadi Z, Kamanna K 3 Biotech. 2025; 15(1):30.

PMID: 39760002 PMC: 11699011. DOI: 10.1007/s13205-024-04188-z.

Cord blood platelet-rich plasma: proteomics analysis for ophthalmic applications.

Savastano M, Giannuzzi F, Savastano A, Cestrone V, Boselli F, Carla M Clin Proteomics. 2025; 22(1):1.

PMID: 39754030 PMC: 11699781. DOI: 10.1186/s12014-024-09524-2.

Current Developments in NK Cell Engagers for Cancer Immunotherapy: Focus on CD16A and NKp46.

Shin M, Oh E, Minn D Immune Netw. 2024; 24(5):e34.

PMID: 39513028 PMC: 11538608. DOI: 10.4110/in.2024.24.e34.

References

Pillay V, Gan H, Scott A . Antibodies in oncology. N Biotechnol. 2011; 28(5):518-29. DOI: 10.1016/j.nbt.2011.03.021. View

Kim D, Jung H, Kim J, Lee J, Yang D, Park Y . FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood. 2006; 108(8):2720-5. DOI: 10.1182/blood-2006-01-009480. View

Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G . Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol. 2008; 26(11):1789-96. DOI: 10.1200/JCO.2007.14.8957. View

Clynes R . Antitumor antibodies in the treatment of cancer: Fc receptors link opsonic antibody with cellular immunity. Hematol Oncol Clin North Am. 2006; 20(3):585-612. DOI: 10.1016/j.hoc.2006.02.010. View

Dornan D, Spleiss O, Yeh R, Duchateau-Nguyen G, Dufour A, Zhi J . Effect of FCGR2A and FCGR3A variants on CLL outcome. Blood. 2010; 116(20):4212-22. DOI: 10.1182/blood-2010-03-272765. View

Qiu L, Mao C, Zhang J, Zhu X, Liao R, Xue K . Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies. Eur J Cancer. 2010; 46(15):2781-7. DOI: 10.1016/j.ejca.2010.05.022. View

Warmerdam P, van de Winkel J, Vlug A, Westerdaal N, Capel P . A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding. J Immunol. 1991; 147(4):1338-43. View

Paez D, Pare L, Espinosa I, Salazar J, del Rio E, Barnadas A . Immunoglobulin G fragment C receptor polymorphisms and KRAS mutations: are they useful biomarkers of clinical outcome in advanced colorectal cancer treated with anti-EGFR-based therapy?. Cancer Sci. 2010; 101(9):2048-53. PMC: 11158139. DOI: 10.1111/j.1349-7006.2010.01621.x. View

Prochazka V, Papajik T, Gazdova J, Divoka M, Rozmanova S, Faber E . FcγRIIIA receptor genotype does not influence an outcome in patients with follicular lymphoma treated with risk-adapted immunochemotherapy. Neoplasma. 2011; 58(3):263-70. DOI: 10.4149/neo_2011_03_263. View

10.

Manches O, Lui G, Chaperot L, Gressin R, Molens J, Jacob M . In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood. 2002; 101(3):949-54. DOI: 10.1182/blood-2002-02-0469. View

11.

Ravetch J, Perussia B . Alternative membrane forms of Fc gamma RIII(CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions. J Exp Med. 1989; 170(2):481-97. PMC: 2189395. DOI: 10.1084/jem.170.2.481. View

12.

Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C . Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?. Br J Cancer. 2006; 94(2):259-67. PMC: 2361112. DOI: 10.1038/sj.bjc.6602930. View

13.

Rodriguez J, Zarate R, Bandres E, Boni V, Hernandez A, Sola J . Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Eur J Cancer. 2012; 48(12):1774-80. DOI: 10.1016/j.ejca.2012.01.007. View

14.

Zhang W, Gordon M, Schultheis A, Yang D, Nagashima F, Azuma M . FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol. 2007; 25(24):3712-8. DOI: 10.1200/JCO.2006.08.8021. View

15.

Cartron G, Trappe R, Solal-Celigny P, Hallek M . Interindividual variability of response to rituximab: from biological origins to individualized therapies. Clin Cancer Res. 2011; 17(1):19-30. DOI: 10.1158/1078-0432.CCR-10-1292. View

16.

Clynes R, Towers T, Presta L, Ravetch J . Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000; 6(4):443-6. DOI: 10.1038/74704. View

17.

Alderson K, Sondel P . Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol. 2011; 2011:379123. PMC: 3110303. DOI: 10.1155/2011/379123. View

18.

Bibeau F, Lopez-Crapez E, Di Fiore F, Thezenas S, Ychou M, Blanchard F . Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol. 2009; 27(7):1122-9. DOI: 10.1200/JCO.2008.18.0463. View

19.

Lejeune J, Thibault G, Ternant D, Cartron G, Watier H, Ohresser M . Evidence for linkage disequilibrium between Fcgamma RIIIa-V158F and Fcgamma RIIa-H131R polymorphisms in white patients, and for an Fcgamma RIIIa-restricted influence on the response to therapeutic antibodies. J Clin Oncol. 2008; 26(33):5489-91. DOI: 10.1200/JCO.2008.19.4118. View

20.

Koene H, Kleijer M, Algra J, Roos D, von dem Borne A, de Haas M . Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood. 1997; 90(3):1109-14. View