> Detailanzeige

Ravi, Rajani; Noonan, Kimberly A.; Pham, Vui; Bedi, Rishi; Zhavoronkov, Alex; Ozerov, Ivan V.; Makarev, Eugene; V. Artemov, Artem; Wysocki, Piotr T.; Mehra, Ranee; Nimmagadda, Sridhar; Marchionni, Luigi; Sidransky, David; Borrello, Ivan M.; Izumchenko, Evgeny; Bedi, Atul

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

Literatur-
verwaltung

Zur
Merkliste

Lösche von
Merkliste

Per Whatsapp teilen

Schließen

Merkliste



Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
  • Medientyp: E-Artikel
  • Titel: Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy
  • Beteiligte: Ravi, Rajani; Noonan, Kimberly A.; Pham, Vui; Bedi, Rishi; Zhavoronkov, Alex; Ozerov, Ivan V.; Makarev, Eugene; V. Artemov, Artem; Wysocki, Piotr T.; Mehra, Ranee; Nimmagadda, Sridhar; Marchionni, Luigi; Sidransky, David; Borrello, Ivan M.; Izumchenko, Evgeny; Bedi, Atul
  • Erschienen: Springer Science and Business Media LLC, 2018
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-017-02696-6
  • ISSN: 2041-1723
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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<jats:sup>+</jats:sup> and T<jats:sub>H</jats:sub>1 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 (<jats:italic>a</jats:italic>-CTLA4-TGFβRII<jats:italic>ecd</jats:italic> and <jats:italic>a</jats:italic>-PDL1-TGFβRII<jats:italic>ecd</jats:italic>). <jats:italic>a</jats:italic>-CTLA4-TGFβRII<jats:italic>ecd</jats:italic> is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, <jats:italic>a</jats:italic>-PDL1-TGFβRII<jats:italic>ecd</jats:italic> 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.</jats:p>
  • Zugangsstatus: Freier Zugang