Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2018 Mar 27

PMID 29576375

Citations 326

Authors

Frederick Arce Vargas

Andrew J S Furness

Kevin Litchfield

Kroopa Joshi

Rachel Rosenthal

Ehsan Ghorani

Isabelle Solomon

Marta H Lesko

Nora Ruef

Claire Roddie

Jake Y Henry

Lavinia Spain

Assma Ben Aissa

Andrew Georgiou

Yien Ning Sophia Wong

Myles Smith

Dirk Strauss

Andrew Hayes

David Nicol

Tim OBrien

Linda Martensson

Anne Ljungars

Ingrid Teige

Bjorn Frendeus

Martin Pule

Teresa Marafioti

Martin Gore

James Larkin

Samra Turajlic

Charles Swanton

Karl S Peggs

Sergio A Quezada

Affiliations

Soon will be listed here.

Abstract

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8 to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.

Citing Articles

pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies.

Zhang M, Li J, Yan K, Zhou H, Mei S, Wang B Proc Natl Acad Sci U S A. 2025; 122(8):e2422731122.

PMID: 39964714 PMC: 11874271. DOI: 10.1073/pnas.2422731122.

Single cell suppression profiling of human regulatory T cells.

Sondergaard J, Tulyeu J, Priest D, Sakaguchi S, Wing J Nat Commun. 2025; 16(1):1325.

PMID: 39900891 PMC: 11791207. DOI: 10.1038/s41467-024-55746-1.

Engineered ipilimumab variants that bind human and mouse CTLA-4.

Robison B, Diong S, Kumar A, Moon T, Chang O, Chau B MAbs. 2025; 17(1):2451296.

PMID: 39849917 PMC: 11776466. DOI: 10.1080/19420862.2025.2451296.

Advances in the understanding and therapeutic manipulation of cancer immune responsiveness: a Society for Immunotherapy of Cancer (SITC) review.

Cesano A, Augustin R, Barrea L, Bedognetti D, Bruno T, Carturan A J Immunother Cancer. 2025; 13(1).

PMID: 39824527 PMC: 11749597. DOI: 10.1136/jitc-2024-008876.

Anti-CTLA4 treatment reduces lymphedema risk potentially through a systemic expansion of the FOXP3 T population.

Wolf S, Madanchi M, Turko P, Hollmen M, Tugues S, von Atzigen J Nat Commun. 2024; 15(1):10784.

PMID: 39737964 PMC: 11686037. DOI: 10.1038/s41467-024-55002-6.

References

Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky J, Desrichard A . Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23):2189-2199. PMC: 4315319. DOI: 10.1056/NEJMoa1406498. View

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

Weng W, Levy R . Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003; 21(21):3940-7. DOI: 10.1200/JCO.2003.05.013. View

Robert C, Ribas A, Wolchok J, Hodi F, Hamid O, Kefford R . Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384(9948):1109-17. DOI: 10.1016/S0140-6736(14)60958-2. 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

Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z . CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008; 322(5899):271-5. DOI: 10.1126/science.1160062. View

Lazar G, Dang W, Karki S, Vafa O, Peng J, Hyun L . Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A. 2006; 103(11):4005-10. PMC: 1389705. DOI: 10.1073/pnas.0508123103. View

De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C . Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity. 2016; 45(5):1135-1147. PMC: 5119953. DOI: 10.1016/j.immuni.2016.10.021. View

Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L . Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol. 2006; 177(7):4376-83. PMC: 6108417. DOI: 10.4049/jimmunol.177.7.4376. View

10.

Smith P, DiLillo D, Bournazos S, Li F, Ravetch J . Mouse model recapitulating human Fcγ receptor structural and functional diversity. Proc Natl Acad Sci U S A. 2012; 109(16):6181-6. PMC: 3341029. DOI: 10.1073/pnas.1203954109. View

11.

Comin-Anduix B, Escuin-Ordinas H, Ibarrondo F . Tremelimumab: research and clinical development. Onco Targets Ther. 2016; 9:1767-76. PMC: 4809326. DOI: 10.2147/OTT.S65802. View

12.

Hodi F, Butler M, Oble D, Seiden M, Haluska F, Kruse A . Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008; 105(8):3005-10. PMC: 2268575. DOI: 10.1073/pnas.0712237105. View

13.

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

14.

Schneider-Merck T, Lammerts van Bueren J, Berger S, Rossen K, van Berkel P, Derer S . Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibody-dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol. 2009; 184(1):512-20. DOI: 10.4049/jimmunol.0900847. View

15.

Sarmay G, Lund J, Rozsnyay Z, Gergely J, Jefferis R . Mapping and comparison of the interaction sites on the Fc region of IgG responsible for triggering antibody dependent cellular cytotoxicity (ADCC) through different types of human Fc gamma receptor. Mol Immunol. 1992; 29(5):633-9. DOI: 10.1016/0161-5890(92)90200-h. View

16.

Furness A, Vargas F, Peggs K, Quezada S . Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatory antibodies. Trends Immunol. 2014; 35(7):290-8. DOI: 10.1016/j.it.2014.05.002. View

17.

Van Allen E, Miao D, Schilling B, Shukla S, Blank C, Zimmer L . Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015; 350(6257):207-211. PMC: 5054517. DOI: 10.1126/science.aad0095. View

18.

Hodi F, ODay S, Mcdermott D, Weber R, Sosman J, Haanen J . Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711-23. PMC: 3549297. DOI: 10.1056/NEJMoa1003466. View

19.

Selby M, Engelhardt J, Quigley M, Henning K, Chen T, Srinivasan M . Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2014; 1(1):32-42. DOI: 10.1158/2326-6066.CIR-13-0013. View

20.

Wu J, Edberg J, Redecha P, Bansal V, Guyre P, Coleman K . A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest. 1997; 100(5):1059-70. PMC: 508280. DOI: 10.1172/JCI119616. View