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<p>HexaBody-CD27 (GEN1053/BNT313) is an investigational novel agonistic CD27 antibody engineered to enhance T-cell costimulation and promote antitumor immunity. Through the introduction of a hexamerization-enhancing mutation in the IgG Fc domain, HexaBody-CD27 was designed to drive clustering and activation of CD27 via intermolecular Fc:Fc interactions between membrane-bound antibodies, independent of crosslinking by FcγR-bearing cells. HexaBody-CD27 carries an Fc-silencing mutation to prevent T-cell depletion through Fc-mediated effector functions.&#xa0;In vitro, HexaBody-CD27 induced CD27 receptor signaling independent of FcγR-mediated crosslinking in a reporter assay. It also enhanced T-cell proliferation, cytotoxic activity and proinflammatory cytokine secretion in primary human lymphocytes. In contrast to benchmark IgG1 CD27 antibodies, HexaBody-CD27 did not induce phagocytosis of T cells in vitro. HexaBody-CD27 promoted ex vivo tumor infiltrating lymphocyte (TIL) expansion in non-small cell lung cancer (NSCLC) specimens, in particular of CD8<sup>+</sup> TILs. The combination of HexaBody-CD27 with an anti-PD-1 antibody enhanced T-cell proliferation, cytokine secretion, and cytotoxic activity in vitro compared to either compound alone. In conclusion, HexaBody-CD27 enhanced T-cell activation and effector functions in an FcγR-crosslinking-independent manner, without inducing T-cell depletion. The immune agonist activity of HexaBody-CD27 was potentiated in combination with PD-1 blockade.</p>

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A hexamerization-enhanced, Fc-silenced agonistic CD27 antibody amplifies T-cell effector functions as single agent and in combination with PD-1 blockade

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月24日

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  • Işıl Altıntaş,
  • Kristina B. Nürmberger,
  • Andrea Imle,
  • Anna-Lena Krause,
  • Marike M. van Beuge,
  • Aras Toker,
  • Andreea Ioan-Facsinay,
  • Jordan Blum,
  • Alexander Muik,
  • Frank J. Beurskens,
  • Rob N. de Jong,
  • David P. E. Satijn,
  • Friederike Gieseke,
  • Bart-Jan de Kreuk,
  • Maarten van der Kroef,
  • Sina Fellermeier-Kopf,
  • Tahamtan Ahmadi,
  • Özlem Türeci,
  • Esther C. W. Breij,
  • Uğur Şahin

摘要

HexaBody-CD27 (GEN1053/BNT313) is an investigational novel agonistic CD27 antibody engineered to enhance T-cell costimulation and promote antitumor immunity. Through the introduction of a hexamerization-enhancing mutation in the IgG Fc domain, HexaBody-CD27 was designed to drive clustering and activation of CD27 via intermolecular Fc:Fc interactions between membrane-bound antibodies, independent of crosslinking by FcγR-bearing cells. HexaBody-CD27 carries an Fc-silencing mutation to prevent T-cell depletion through Fc-mediated effector functions. In vitro, HexaBody-CD27 induced CD27 receptor signaling independent of FcγR-mediated crosslinking in a reporter assay. It also enhanced T-cell proliferation, cytotoxic activity and proinflammatory cytokine secretion in primary human lymphocytes. In contrast to benchmark IgG1 CD27 antibodies, HexaBody-CD27 did not induce phagocytosis of T cells in vitro. HexaBody-CD27 promoted ex vivo tumor infiltrating lymphocyte (TIL) expansion in non-small cell lung cancer (NSCLC) specimens, in particular of CD8+ TILs. The combination of HexaBody-CD27 with an anti-PD-1 antibody enhanced T-cell proliferation, cytokine secretion, and cytotoxic activity in vitro compared to either compound alone. In conclusion, HexaBody-CD27 enhanced T-cell activation and effector functions in an FcγR-crosslinking-independent manner, without inducing T-cell depletion. The immune agonist activity of HexaBody-CD27 was potentiated in combination with PD-1 blockade.