MK-6, a novel not-α IL-2, elicits a potent antitumor activity by improving the effector to regulatory T cell balance

Maki Kobayashi, Katsuhiko Kojima, Kazutaka Murayama, Yuji Amano, Takashi Koyama, Naoko Ogama, Toshikazu Takeshita, Tatsuro Fukuhara, Nobuyuki Tanaka

Research output: Contribution to journalArticlepeer-review

Abstract

IL-2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti-immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL-2, Mutakine-6 (MK-6), with reduced IL-2Rα–binding capability. MK-6 induced comparable cell growth potential toward IL-2Rβγ–positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL-2, in vivo administration of MK-6 produced minimal adverse effects. Using CT26 and B16F10-syngeneic tumor models, we found MK-6 was highly efficacious on tumor regression. Serum albumin conjugation to MK-6 prolonged in vivo half-life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor-infiltrating leukocytes analysis revealed that albumin-fused MK-6 increased the ratio of effector CD8+ T cells to CD4+ Treg cells. These results demonstrated that MK-6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation.

Original languageEnglish
Pages (from-to)4478-4489
Number of pages12
JournalCancer science
Volume112
Issue number11
DOIs
Publication statusPublished - 2021 Nov

Keywords

  • cancer immunotherapy
  • cytokines
  • IL-2 Mutein
  • regulatory T cells
  • tumor-infiltrating lymphocytes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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