Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy
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Abstract A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH1 cells. To address this therapeutic challenge, we invent bifunctional antibody–ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.
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Further engineering led to the development of a smaller ligand trap with a 100-1000-fold increased ligand-binding efficacy.
“Further engineering led to the development of a smaller ligand trap with a 100–1000-fold increased ligand-binding efficacy311.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [311]
Pharmacological inhibition of TGFb or its receptors resolves immunological exclusion and improves antigen presentation by malignant cells, leading to potent anticancer immune responses with ICIs toward disease eradication and protective immunological memory in mouse models of melanoma, colorectal, breast, and squamous cell carcinoma.
“pharmacological inhibition of TGFb or its receptors resolves immunological exclusion and improves antigen presentation by malignant cells, culminating in potent anticancer immune responses that can be actioned with ICIs toward disease eradication and establishment of protective immunological memory, at least in mouse models of melanoma”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Ravi et al., 2018
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- Authors
- Ravi, R., Noonan, K. A., Pham, V., Bedi, R., Zhavoronkov, A., Ozerov, I. V., Makarev, E., V. Artemov, A., Wysocki, P. T., Mehra, R., Nimmagadda, S., Marchionni, L., Sidransky, D., Borrello, I. M., Izumchenko, E., & Bedi, A.
- Affiliations
- Johns Hopkins University (US)
- Stanford University (US)
- Corresponding author
- Bedi, Atul
- ORCID
- Venue
- Nature Communications
- Published
- 2018-02-21
- Volume
- 9
- Issue
- 1
- Pages
- 741-741
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5821872
- OpenAlex
- W2789421415
- Cited by
- 325
- References
- 74
- Citations by year
- 2026: 13 · 2025: 26 · 2024: 37 · 2023: 57 · 2022: 45 · 2021: 52 · 2020: 56 · 2019: 17 · 2018: 21
- FWCI
- 13.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (DE019032)
- National Cancer Institute (R01CA184199)
- National Institute of Dental and Craniofacial Research (P50DE019032)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TGFBR2, CTLA-4, PD-L1, immune checkpoint inhibitors, regulatory T cells, tumor microenvironment, cancer immunotherapy, Treg differentiation, immune tolerance, antitumor efficacy
- MeSH terms
- Animals, Antibodies, Breast Neoplasms, Female, Humans, Immunotherapy, Melanoma, Cohort Studies, Transforming Growth Factor beta, Lymphocytes, Tumor-Infiltrating, Mice, Inbred NOD, Receptors, Transforming Growth Factor beta, Th1 Cells, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Th17 Cells, B7-H1 Antigen, CTLA-4 Antigen
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