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Enhanced affinity for the IL-2 receptor β subunit potently increases antitumor efficacy of IL-2 across various tumor

Ernesto Relova-Hernández1, Ana Beatriz Díaz-Bravo1, Rodrigo Pedroso2,3

  • 1Center of Molecular Immunology, Havana, Cuba.

Journal of Immunology (Baltimore, Md. : 1950)
|August 28, 2025
PubMed

Insights

A novel interleukin-2 (IL-2) variant, superbeta 834 (SB834Fc), demonstrates potent antitumor effects in preclinical models. This engineered IL-2 mutein selectively stimulates effector T cells, offering a promising new avenue for cancer immunotherapy with reduced toxicity.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • High-dose recombinant interleukin-2 (IL-2) cancer therapy is limited by toxicity and regulatory T cell expansion.
  • Interleukin-2 receptor (IL-2R) affinity modulation via IL-2 muteins offers selective effector cell stimulation and reduced toxicity.
  • Previous work generated IL-2 muteins with increased affinity for the IL-2R beta chain using phage display, showing improved developability and in vivo efficacy as Fc-fusion proteins (IL-2Fc).

Purpose of the Study:

  • To comprehensively characterize the properties of an improved IL-2 mutein, superbeta 834 (SB834Fc).
  • To evaluate the antitumor efficacy and immune-stimulating potential of SB834Fc compared to IL-2Fc in preclinical cancer models.
  • To assess the translational value of SB834Fc for human cancer immunotherapy.

Main Methods:

  • Generation of IL-2 muteins with altered IL-2R affinity using phage display technology.
  • Construction and evaluation of Fc-fusion proteins incorporating IL-2 muteins (IL-2Fc and SB834Fc).
  • Assessment of antitumor effects in five murine tumor models (3LL-D122, B16F10, CT26, MC38, 4T1).
  • Analysis of T cell stimulation (effector and regulatory T cells) in spleen and tumor microenvironment.
  • In vitro proliferation assays using CD8+ T cells from human healthy donors.

Main Results:

  • SB834Fc exhibited a significantly stronger antitumor effect than IL-2Fc across five murine tumor models, even at very low doses.
  • SB834Fc demonstrated therapeutic antitumor effects as a single agent in a therapeutic injection scheme.
  • SB834Fc induced robust stimulation of effector T cells in the spleen and tumor microenvironment, exceeding IL-2Fc, while maintaining similar regulatory T cell stimulation levels.
  • SB834Fc induced proliferation in CD8+ T cells from human donors, indicating translational potential.

Conclusions:

  • SB834Fc represents a potent IL-2 mutein with enhanced antitumor efficacy and a favorable immune-stimulating profile.
  • SB834Fc overcomes limitations of traditional IL-2 therapy by selectively boosting effector T cells with reduced toxicity.
  • The SB834Fc fusion protein is a promising candidate for developing novel IL-2-based cancer immunotherapies.
Keywords:
IL-2 muteinIL-2FcIL-2Rβeffector cellssuperagonist

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