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Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
- Source :
-
Cancer cell [Cancer Cell] 2018 Apr 09; Vol. 33 (4), pp. 649-663.e4. Date of Electronic Publication: 2018 Mar 22. - Publication Year :
- 2018
-
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 <superscript>+</superscript> 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.<br /> (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 33
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 29576375
- Full Text :
- https://doi.org/10.1016/j.ccell.2018.02.010