1. Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
- Author
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Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, Henry JY, Spain L, Ben Aissa A, Georgiou A, Wong YNS, Smith M, Strauss D, Hayes A, Nicol D, O'Brien T, Mårtensson L, Ljungars A, Teige I, Frendéus B, Pule M, Marafioti T, Gore M, Larkin J, Turajlic S, Swanton C, Peggs KS, and Quezada SA
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological pharmacology, CTLA-4 Antigen antagonists & inhibitors, Cell Line, Tumor, Female, Humans, Ipilimumab administration & dosage, Ipilimumab pharmacology, Melanoma genetics, Melanoma immunology, Mice, Receptors, IgG metabolism, Treatment Outcome, Xenograft Model Antitumor Assays, Antineoplastic Agents, Immunological administration & dosage, Melanoma drug therapy, Polymorphism, Single Nucleotide, Receptors, IgG genetics, T-Lymphocytes, Regulatory immunology
- 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., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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