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Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells
Published version of a preprint
Abstract
Antitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the immunoglobulin constant region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies. Anti-CTLA-4 antibody containing the murine immunoglobulin G (IgG)2a constant region exhibits enhanced antitumor activity in subcutaneous established MC38 and CT26 colon adenocarcinoma tumor models compared with anti-CTLA-4 containing the IgG2b constant region. Interestingly, anti-CTLA-4 antibodies containing mouse IgG1 or a mutated mouse IgG1-D265A, which eliminates binding to all Fcγ receptors (FcγR), do not show antitumor activity in these models. Assessment of Teff and Treg populations at the tumor and in the periphery showed that anti-CTLA-4-IgG2a mediated a rapid and dramatic reduction of Tregs at the tumor site, whereas treatment with each of the isotypes expanded Tregs in the periphery. Expansion of CD8+ Teffs is observed with both the IgG2a and IgG2b anti-CTLA-4 isotypes, resulting in a superior Teff to Treg ratio for the IgG2a isotype. These data suggest that anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral Tregs along with concomitant activation of Teffs. Cancer Immunol Res; 1(1); 32–42. ©2013 AACR.
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Anti-CTLA-4 antibodies deplete intratumoral Tregs, possibly through antibody-dependent cell-mediated cytotoxicity, leading to enhanced anti-tumor responses.
“Anti- CTLA-4antibodies have been shown to deplete intratumoral Tregs, possibly through antibody-dependent cell-mediated cytotoxicity, leading to enhanced anti-tumor responses [120].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [120]
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Metadata
- Authors
- Selby, M. J., Engelhardt, J. J., Quigley, M., Henning, K. A., Chen, T., Srinivasan, M., & Korman, A. J.
- Affiliations
- Bristol-Myers Squibb (United States) (US)
- Authors' Affiliation: Bristol-Myers Squibb Company, Redwood City, California
- Venue
- Cancer Immunology Research
- Published
- 2013-07-01
- Volume
- 1
- Issue
- 1
- Pages
- 32-42
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- OpenAlex
- W2101581360
- Cited by
- 857
- References
- 46
- Citations by year
- 2026: 23 · 2025: 40 · 2024: 52 · 2023: 63 · 2022: 79 · 2021: 80 · 2020: 92 · 2019: 89 · 2018: 79 · 2017: 69 · 2016: 73 · 2015: 57 · 2014: 46 · 2013: 14
- FWCI
- 33.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Keywords
- anti-CTLA-4 antibody, CTLA-4, antibody isotypes, regulatory T cells, CD8+ effector T cells, Fcγ receptor binding, colon adenocarcinoma, tumor immunology, immune checkpoint blockade
- MeSH terms
- Animals, Antibodies, Monoclonal, Colonic Neoplasms, Cricetulus, Disease Models, Animal, Female, Immunoglobulin G, Mice, Inbred BALB C, Mice, Inbred C57BL, Random Allocation, CHO Cells, T-Lymphocytes, Regulatory, Mice, CTLA-4 Antigen
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 ›
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