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.

• Klíčová slova
• IL-2, PD-1, cancer, cytotoxic T cells, immunotherapy, regulatory T cell,
• MeSH
• CD8-pozitivní T-lymfocyty * MeSH
• cytotoxické T-lymfocyty MeSH
• fenotyp MeSH
• imunoterapie MeSH
• interleukin-2 * terapeutické užití   metabolismus   MeSH
• myši MeSH
• regulační T-lymfocyty MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• 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.

• Klíčová slova
• CP: Immunology, antibody, autoimmune disease, cytokine, immunocytokine, interleukin-2, molecular therapeutics, regulatory T cell,
• MeSH
• autoimunitní nemoci * MeSH
• cytokiny metabolismus   MeSH
• interleukin-2 * MeSH
• lidé MeSH
• myši MeSH
• protilátky metabolismus   MeSH
• regulační T-lymfocyty MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• cytokiny MeSH
• interleukin-2 * MeSH
• protilátky MeSH

Complexes of IL-2 and JES6-1 mAb (IL-2/JES6) provide strong sustained IL-2 signal selective for CD25+ cells and thus they potently expand Treg cells. IL-2/JES6 are effective in the treatment of autoimmune diseases and in protecting against rejection of pancreatic islet allografts. However, we found that IL-2/JES6 also dramatically increase sensitivity to LPS-mediated shock in C57BL/6 mice. We demonstrate here that this phenomenon is dependent on endogenous IFN-γ and T cells, as it is not manifested in IFN-γ deficient and nude mice, respectively. Administration of IL-2/JES6 leads to the emergence of CD25+Foxp3-CD4+ and CD25+Foxp3-CD8+ T cells producing IFN-γ in various organs, particularly in the liver. IL-2/JES6 also increase counts of CD11b+CD14+ cells in the blood and the spleen with higher sensitivity to LPS in terms of TNF-α production and induce expression of CD25 in these cells. These findings indicate safety issue for potential use of IL-2/JES6 or similar IL-2-like immunotherapeutics.

• Klíčová slova
• CD25, IFN-γ, LPS, T cells, hyperreactivity, il-2/anti-il-2 mab complexes, immunology, inflammation, mouse,
• MeSH
• interferon gama nedostatek   MeSH
• interleukin-2 metabolismus   MeSH
• lipopolysacharidy metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši nahé MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• IFNG protein, mouse MeSH Prohlížeč
• interferon gama MeSH
• interleukin-2 MeSH
• lipopolysacharidy MeSH

IL-2 has been used to treat diseases ranging from cancer to autoimmune disorders, but its concurrent immunostimulatory and immunosuppressive effects hinder efficacy. IL-2 orchestrates immune cell function through activation of a high-affinity heterotrimeric receptor (composed of IL-2Rα, IL-2Rβ, and common γ [γc]). IL-2Rα, which is highly expressed on regulatory T (TReg) cells, regulates IL-2 sensitivity. Previous studies have shown that complexation of IL-2 with the JES6-1 Ab preferentially biases cytokine activity toward TReg cells through a unique mechanism whereby IL-2 is exchanged from the Ab to IL-2Rα. However, clinical adoption of a mixed Ab/cytokine complex regimen is limited by stoichiometry and stability concerns. In this study, through structure-guided design, we engineered a single agent fusion of the IL-2 cytokine and JES6-1 Ab that, despite being covalently linked, preserves IL-2 exchange, selectively stimulating TReg expansion and exhibiting superior disease control to the mixed IL-2/JES6-1 complex in a mouse colitis model. These studies provide an engineering blueprint for resolving a major barrier to the implementation of functionally similar IL-2/Ab complexes for treatment of human disease.

• MeSH
• aktivace lymfocytů MeSH
• autoimunitní nemoci imunologie   terapie   MeSH
• cytokiny genetika   imunologie   metabolismus   MeSH
• imunoterapie metody   MeSH
• kolitida imunologie   terapie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• proliferace buněk MeSH
• proteinové inženýrství MeSH
• protilátky genetika   metabolismus   MeSH
• receptory interleukinu-2 imunologie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• rekombinantní fúzní proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• cytokiny MeSH
• protilátky MeSH
• receptory interleukinu-2 MeSH
• rekombinantní fúzní proteiny MeSH

The in vivo biological activity of IL-2 can be dramatically increased by complexing with anti-IL-2 mAb. Moreover, IL-2/anti-IL-2 mAb immunocomplexes selectively stimulate different subsets of immune cells, depending on the clone of anti-IL-2 mAb that is used. Thus, IL-2/S4B6 mAb complexes strongly stimulate CD122high populations, namely NK and memory CD8+ T cells. They also intermediately stimulate Treg cells. Conversely, IL-2/JES6.1 mAb immunocomplexes have no stimulatory activity for CD122high populations. However, they potently and highly selectively stimulate CD25+ cells (i.e., Treg and activated T cells). IL-2/S4B6 mAb immunocomplexes have also been shown to possess antitumor activity in various mouse tumor models.

• Klíčová slova
• Anti-IL-2 mAb, IL-2, cancer immunotherapy, immunocomplexes, selective stimulatory activity,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates immune cell homeostasis and has been used to treat a range of disorders including cancer and autoimmune disease. IL-2 signals via interleukin-2 receptor-β (IL-2Rβ):IL-2Rγ heterodimers on cells expressing high (regulatory T cells, Treg) or low (effector cells) amounts of IL-2Rα (CD25). When complexed with IL-2, certain anti-cytokine antibodies preferentially stimulate expansion of Treg (JES6-1) or effector (S4B6) cells, offering a strategy for targeted disease therapy. We found that JES6-1 sterically blocked the IL-2:IL-2Rβ and IL-2:IL-2Rγ interactions, but also allosterically lowered the IL-2:IL-2Rα affinity through a "triggered exchange" mechanism favoring IL-2Rα(hi) Treg cells, creating a positive feedback loop for IL-2Rα(hi) cell activation. Conversely, S4B6 sterically blocked the IL-2:IL-2Rα interaction, while also conformationally stabilizing the IL-2:IL-2Rβ interaction, thus stimulating all IL-2-responsive immune cells, particularly IL-2Rβ(hi) effector cells. These insights provide a molecular blueprint for engineering selectively potentiating therapeutic antibodies.

• MeSH
• autoimunitní nemoci imunologie   MeSH
• interleukin-2 chemie   genetika   imunologie   metabolismus   MeSH
• kompetitivní vazba účinky léků   MeSH
• lidé MeSH
• molekulární modely * MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• progrese nemoci MeSH
• proliferace buněk účinky léků   MeSH
• protilátky chemie   imunologie   farmakologie   MeSH
• průtoková cytometrie MeSH
• regulace genové exprese imunologie   MeSH
• regulační T-lymfocyty cytologie   účinky léků   imunologie   MeSH
• signální transdukce účinky léků   MeSH
• T-lymfocyty - podskupiny cytologie   účinky léků   imunologie   MeSH
• terciární struktura proteinů MeSH
• vazba proteinů účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• interleukin-2 MeSH
• protilátky MeSH