Interleukin 15 is a pleiotropic cytokine of the four α helix bundle family. Binding to a heterotrimeric receptor complex, which consists of a unique, high affinity IL‑15Rα‑chain and IL-2/IL-15Rβ and IL‑2Rγ chains, IL‑15 activates signaling pathways leading to activation and proliferation of T and B cells, as well as natural killer cells. At the same time, IL‑15 protects effector cells from T regulatory cells and does not induce immune tolerance. The significant regulatory action of IL‑15 on the immune system provides new opportunities for development of anti‑cancer therapies. As documented in many experiments using different tumor models, IL‑15 enhances antitumor effects. To improve the efficiency of IL‑15, several strategies, including combination with other anti‑cancer therapies such as chemotherapy, additional use of antibodies (anti‑PD‑L1, anti‑CTLA‑4, anti‑CD40), or other cytokines, have been evaluated. Increased anti‑tumor activity can also be obtained by using IL‑15 agonists. However, acting as a growth factor for immune cells but also for tumor cells, IL‑15 may promote their proliferation, survival and dissemination. Of significance seems the role of IL‑15 in the pathogenesis of hematological malignancies, which is due to the involvement in the proliferation and differentiation of NK, T and B cells. Currently, several experimental strategies are available to block biological activity of IL‑15. Among compounds inhibiting the activity of IL‑15 are not only monoclonal antibodies interacting directly with the cytokine or with IL‑15R subunits, but also mutant forms of IL‑15 and protein constructs.

2012-01-01·Journal of peptide science : an official publication of the European Peptide Society4区 · 生物学

Enhancement of the inhibitory effect of an IL‐15 antagonist peptide by alanine scanning

4区 · 生物学

Article

作者: Chico, Araceli ; Aguero, Celia Aurora Arrieta ; Pérez, Haydee Gerónimo ; Ojeda, Miriam Ojeda ; Álvarez, Yunier Rodríguez ; Acosta, Osvaldo Reyes ; Nieto, Gerardo Guillen ; Estévez, Miguel ; Pérez, Hilda Garay ; Savio, Alicia Santos

IL‐15 is a proinflammatory cytokine that acts early in the inflammatory response and has been associated with several autoimmune diseases including rheumatoid arthritis, where it had been proposed as a therapeutic target. We recently reported an IL‐15 antagonist peptide corresponding to sequence 36–45 of IL‐15 (KVTAMKCFLL) named P8, which specifically binds to IL‐15Rα and inhibits IL‐15 biological activity with a half maximal inhibitory concentration (IC50) of 130 µ m in CTLL‐2 proliferation assay. In order to improve binding of peptide P8 to the receptor IL‐15Rα, we used an Ala scan strategy to study contribution of each individual amino acid to the peptide's antagonist effect. Here, we found that Phe and Cys are important for peptide binding to IL‐15Rα. We also investigated other single site mutations and replaced the second Lys in the sequence by the polar non‐charged amino acid threonine. The resulting peptide [K6T]P8 exhibited a higher activity than P8 with an IC50 of 24 µm. We also found that this peptide was more active than peptide P8 in the inhibition of TNFα secretion by synovial cells from rheumatoid arthritis patients. The peptide [K6T]P8 described in this work is a new type of IL‐15 antagonist and constitutes a potential therapeutic agent for rheumatoid arthritis. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.

2009-11-01·Immunology and cell biology3区 · 医学

NK cells enhance the induction of CTL responses by IL‐15 monocyte‐derived dendritic cells

3区 · 医学

Article

作者: Wilkinson, Ray ; Hardy, Melinda Y ; Hart, Derek N J ; Radford, Kristen J ; Vulink, Annelie ; Jongbloed, Sarah L ; Kassianos, Andrew J

Dendritic cells differentiated from monocytes (MoDC) in the presence of GM‐CSF and IL‐15 (IL‐15 MoDC) exhibit superior migration and cytotoxic T‐lymphocyte (CTL) induction compared with MoDC differentiated in IL‐4 and GM‐CSF (IL‐4 MoDC) and are promising candidates for DC immunotherapy. We explored the mechanisms by which IL‐15 MoDC induce CTL. IL‐15 MoDC expressed higher levels of CD40 and secreted high levels of TNF‐α, but little or no IL‐12p70 compared with IL‐4 MoDC. Despite immuno‐selecting monocytes to >97% purity before MoDC generation, a tiny population (0.2%) of natural killer (NK) cells was identified that was increased sevenfold during IL‐15 MoDC, but not IL‐4 MoDC differentiation. These NK cells produced high levels of IFN‐γ and were responsible for the enhanced CTL‐inducing capacity of the IL‐15 MoDC, but not for their increased expression of CD40 or secretion of TNF‐α. Interestingly, a proportion of IL‐15 MoDC were found to express the NK cell marker, CD56, but these did not secrete IFN‐γ. These data implicate a role for small percentages of NK cells in the enhanced capacity of IL‐15 MoDC to induce tumour‐specific CTL independent of IL‐12p70.

项与 TRQ-1501 相关的新闻（医药）

2023-01-19

·GlobeNewswire-Health Care

SOTIO Doses First Patient in AURELIO-05 Phase 2 Trial of Nanrilkefusp Alfa in Combination with Cetuximab

BASEL, Jan. 19, 2023 (GLOBE NEWSWIRE) -- SOTIO Biotech, a clinical stage immuno-oncology company owned by PPF Group, announced today that the first patient was dosed in its Phase 2 AURELIO-05 combination trial of nanrilkefusp alfa (previously known as SOT101), an IL-15 superagonist, and cetuximab in patients with colorectal cancer. “The initiation of this Phase 2 study is an important step in the clinical development of nanrilkefusp alfa. In addition to our previous and ongoing studies to determine the efficacy of nanrilkefusp alfa in combination with checkpoint blockers, we now aim to determine its ability to enhance the antibody dependent cellular cytotoxicity exerted by cetuximab,” said Richard Sachse, M.D., Ph.D., chief medical officer of SOTIO. “If replicated in patients, the increased anti-tumor activity and proliferation of CD8+ T-cells that has been observed in colorectal cancer models treated with IL-15 superagonists could position nanrilkefusp alfa as a safe and effective therapy in combination with cetuximab in this indication. We look forward to evaluating this potential benefit.” The Phase 2 AURELIO-05 trial (NCT05619172) is an open-label, single-arm, multicenter study to evaluate the efficacy and safety of nanrilkefusp alfa in combination with cetuximab in up to 52 patients with RAS wild-type colorectal cancer who are relapsed/refractory or intolerant to prior treatment with irinotecan- and oxaliplatin-containing chemotherapy. The trial will be conducted in approximately 20 specialized sites across Europe. The first patient was dosed at the Gent University Hospital (Belgium), under the supervision of Professor Karen Geboes, head of the Department of Gastrointestinal and Intestinal Diseases. Professor Eric van Cutsem, head of Digestive Oncology at the University Hospital in Leuven (Belgium) and coordinating investigator of the AURELIO-05 trial commented: “Despite recent advances in oncology, patients with advanced refractory colorectal cancer still have poor long term survival rates. Having already demonstrated promising signs of safety and efficacy not only in monotherapy, but also in combination with another approved monoclonal antibody, pembrolizumab, we are pleased to have initiated this critical study to evaluate the potential benefit of nanrilkefusp alfa in combination with cetuximab in this highly underserved patient population.” About nanrilkefusp alfa and IL-15 Superagonist Technology: Nanrilkefusp alfa (previously known as SOT101) is the lead candidate from SOTIO’s IL-15 technology platform. Nanrilkefusp alfa is a subcutaneously administered IL-15 superagonist that is fused to the sushi+ domain of the IL-15 receptor alpha chain. Nanrilkefusp alfa has demonstrated strong preclinical in vivo efficacy in various tumor models showing increased long-term survival and tumor regression, as well as a favorable toxicology profile. Nanrilkefusp alfa has been shown in preclinical models to synergize with checkpoint inhibitors and antibody therapies exerting antibody dependent cellular cytotoxicity (ADCC). Along with Interleukin-2 (IL-2), IL-15 activity is known to increase the number of cytotoxic T cells and NK cells, the two most important cells for driving an anti-cancer immune response. This T and NK cell expansion is the result of IL-15 binding to its IL-15 alpha chain receptor in conjunction with binding to its shared IL-2/IL-15 beta gamma receptor on the surface of T and NK cells. Nanrilkefusp alfa has been precisely designed and optimized for its use as a potent immunotherapy by addressing two important design issues that limit current IL-2 and IL-15 approaches. These include selectively binding only to cytotoxic T and NK cells, while avoiding other cell types associated with adverse events, and stimulating T and NK cells through pulses in cytokine concentrations rather than tonic stimulation. Company contact:Media contact:Richard KapsaMichael TattoryHead of CommunicationLifeSci CommunicationsT:(+420) 224 174 448T:(+1) 609-802-6265M:(+420) 603 280 971mtattory@lifescicomms.comkapsa@sotio.com About SOTIO Biotech SOTIO Biotech is shaping the future of cancer immunotherapies by translating compelling science into patient benefit. The robust SOTIO clinical pipeline includes a differentiated superagonist of the attractive immuno-oncology target IL-15, nanrilkefusp alfa, currently being tested in phase II clinical trials, SOT102, a next generation Claudin-18.2-targeted antibody-drug conjugate (ADC) which entered the clinical phase in 2022, and SOT106, a novel ADC which is currently in preclinical studies. BOXR1030, a GPC3-targeted CAR-T based on proprietary technology designed to improve on the efficacy of CAR-T therapies in the tumor microenvironment, is entering the clinical phase. SOTIO is a member of the PPF Group. For more information, please visit the company’s website at www.sotio.com. SOTIO is a registered trademark of SOTIO Biotech a.s. in selected countries.

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