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Nat Commun. 2018 Feb 21;9(1):741. doi: 10.1038/s41467-017-02696-6.

Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy.

Author information

1
Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
2
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
3
Department of Computer Science, Stanford University, Palo Alto, CA, 94305, USA.
4
Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA.
5
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
6
Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA.
7
Center for Computational Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
8
Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA. abedi1@jhmi.edu.

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.

PMID:
29467463
PMCID:
PMC5821872
DOI:
10.1038/s41467-017-02696-6
[Indexed for MEDLINE]
Free PMC Article

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