Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 15, Pages 3912-3917Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1801524115
Keywords
immunotherapy; CTLA-4; single-domain antibody; cancer; checkpoint blockade
Categories
Funding
- Ludwig Cancer Research Postdoctoral Fellowship
- Claudia Adams Barr Program for Innovative Cancer Research
- De Maag Lever Darm Stichting
- Stichting Bekker-La Bastide-Fonds
- Cancer Research Institute Postdoctoral Fellowship
- Melanoma Research Alliance
- Pew Foundation
- National Institutes of Health (NIH) Grants [HG008325, GM094662, GM094665, DP1-GM106409-03, R01-GM100518-04]
- Albert Einstein Cancer Center Grant [P30CA013330]
- Lustgarten Foundation
- Mentored Clinical Scientist Development Award [1K08DK114563-01]
- NIH Training Grant [1F32CA210568-01]
- Center for the Study of Inflammatory Bowel Disease Grant [DK043351]
- American Gastroenterological Association Research Scholars Award
- NATIONAL CANCER INSTITUTE [F32CA210568, P30CA013330] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG008325] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK043351, K08DK114563] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U54GM094662, DP1GM106409, U01GM094665, R01GM100518] Funding Source: NIH RePORTER
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Ipilimumab, a monoclonal antibody that recognizes cytotoxic T lymphocyte antigen (CTLA)-4, was the first approved check-point-blocking anticancer therapy. In mouse tumor models, the response to antibodies against CTLA-4 depends entirely on expression of the Fc gamma receptor (Fc gamma R), which may facilitate antibody-dependent cellular phagocytosis, but the contribution of simple CTLA-4 blockade remains unknown. To understand the role of CTLA-4 blockade in the complete absence of Fc-dependent functions, we developed H11, a high-affinity alpaca heavy chain-only antibody fragment (VHH) against CTLA-4. The VHH H11 lacks an Fc portion, binds monovalently to CTLA-4, and inhibits interactions between CTLA-4 and its ligand by occluding the ligand-binding motif on CTLA-4 as shown crystallographically. We used H11 to visualize CTLA-4 expression in vivo using whole-animal immuno-PET, finding that surface-accessible CTLA-4 is largely confined to the tumor microenvironment. Despite this, H11-mediated CTLA-4 blockade has minimal effects on antitumor responses. Installation of the murine IgG2a constant region on H11 dramatically enhances its antitumor response. Coadministration of the monovalent H11 VHH blocks the efficacy of a full-sized therapeutic antibody. We were thus able to demonstrate that CTLA-4-binding antibodies require an Fc domain for antitumor effect.
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