Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity

JCI Insight. 2024 Sep 24;9(18):e173469. doi: 10.1172/jci.insight.173469.

Abstract

Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

Keywords: Cancer immunotherapy; Cytokines; Drug therapy; Immunology; Therapeutics.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Female
  • Humans
  • Interleukin-2* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Protein Engineering / methods
  • Recombinant Fusion Proteins* / administration & dosage
  • Recombinant Fusion Proteins* / immunology
  • Recombinant Fusion Proteins* / pharmacology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Interleukin-2
  • Recombinant Fusion Proteins
  • Cytokines