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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / genetics
  • Antibodies / immunology
  • Antibodies / therapeutic use*
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology
  • Breast Neoplasms / therapy*
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / immunology
  • Cohort Studies
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Humans
  • Immunotherapy*
  • Lymphocytes, Tumor-Infiltrating
  • Melanoma / genetics
  • Melanoma / immunology
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred NOD
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology
  • T-Lymphocytes, Regulatory / immunology
  • Th1 Cells / immunology
  • Th17 Cells / immunology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology*

Substances

  • Antibodies
  • B7-H1 Antigen
  • CD274 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta