The therapeutic potential of interleukin (IL)-2 in cancer treatment has been known for decades, yet its widespread adoption in clinical practice remains limited. Recently, chimeric proteins of an anti-PD-1 antibody and suboptimal IL-2 variants were shown to stimulate potent antitumor and antiviral immunity by inducing unique effector CD8+ T cells in mice. A similar subset of cytotoxic T cells is induced by depletion of regulatory T cells (Tregs), suggesting IL-2 sequestration as a major mechanism through which regulatory T cells suppress activated CD8+ T cells. Here, we present our view of how IL-2-based biologicals can boost the antitumor response at a cellular level, and propose that the role of Tregs following such treatments may have been previously overestimated.

• Keywords
• IL-2, PD-1, cancer, cytotoxic T cells, immunotherapy, regulatory T cell,
• MeSH
• CD8-Positive T-Lymphocytes * MeSH
• T-Lymphocytes, Cytotoxic MeSH
• Phenotype MeSH
• Immunotherapy MeSH
• Interleukin-2 * therapeutic use   metabolism   MeSH
• Mice MeSH
• T-Lymphocytes, Regulatory MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Interleukin-2 * MeSH

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

• Keywords
• CP: Immunology, antibody, autoimmune disease, cytokine, immunocytokine, interleukin-2, molecular therapeutics, regulatory T cell,
• MeSH
• Autoimmune Diseases * MeSH
• Cytokines metabolism   MeSH
• Interleukin-2 * MeSH
• Humans MeSH
• Mice MeSH
• Antibodies metabolism   MeSH
• T-Lymphocytes, Regulatory MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Cytokines MeSH
• Interleukin-2 * MeSH
• Antibodies MeSH