FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308385283> ?p ?o ?g. }

• W4308385283 abstract "<h3>Background</h3> IL-2 is a critical cytokine driving immune mediated killing of tumor cells by stimulating both the innate and adaptive immune cells. High-dose IL-2 (aldesleukin) has been approved for the treatment of metastatic melanoma and metastatic renal cell carcinoma, however, the practical use of aldesleukin in the clinic is limited. The short half-life of aldesleukin necessitates a frequent and burdensome treatment schedule for patients. In addition, binding to IL-2Rα on endothelial cells and type 2 innate lymphoid cells is thought to induce severe adverse events associated with vascular leak syndrome. Furthermore, the efficacy of aldesleukin is compromised due to strong activation of immunosuppressive regulatory T cells (Treg) expressing the high-affinity IL-2Rαβγ. To overcome the major limitations of wild-type (WT) IL-2, Exenokine-2 (Exn-2), a fusion protein comprised of a no-α-IL-2 linked to a humanized anti-human serum albumin (HSA) single domain antibody (sdAb), was designed using Anwita’s discovery platform technology. <h3>Methods</h3> Binding affinities were determined using Bio-Layer Interferometry. <i>In vitro</i> potency was assessed using a human primary immune cell-based pSTAT5 assay. <i>In vivo</i> efficacies were assessed in MC38 and B16F10 syngeneic as well as N87 and Raji xenograft mouse models. <h3>Results</h3> The no-α-IL-2 in Exn-2 is a chimera between IL-2 and IL-15 cytokines. The lack of binding with IL-2Rα resulted in limited activation of Treg while retaining the high potency on NK cells and CD8⁺ T cells. The addition of an anti-HSA sdAb in Exn-2 resulted in prolonged systemic exposure with a 30-fold longer half-life in mice as compared to WT IL-2. In syngeneic mouse tumor models, Exn-2 showed strong dose-dependent antitumor efficacy as a single agent with up to 95% reduction in tumor growth, as well as an enhanced efficacy with a high rate up to 66% of complete response when combined with an anti-PD-1 monoclonal antibody. In xenograft models of gastric cancer and lymphoma, Exn-2 significantly potentiated the antitumor activity of Trastuzumab and Rituximab, respectively, demonstrating clinical potential as a combination therapy with ADCC-competent antibodies. In cynomolgus monkeys, Exn-2 was well tolerated and induced robust and sustained expansions of lymphocytes and CD8⁺ T cells while showing negligible effects on eosinophils and Tregs. <h3>Conclusions</h3> Collectively, <i>in vivo</i> efficacies from mouse tumor models as well as the desired pharmacodynamic effects and safety profile observed in cynomolgus monkeys support the first-in-human clinical development of Exn-2. IND-enabling studies for Exn-2 is nearing completion, with GMP lot production completed for the Phase 1 study. <h3>Ethics Approval</h3> The protocol of animal studies has been reviewed and approved by IACUC" @default.
• W4308385283 created "2022-11-11" @default.
• W4308385283 creator A5005420144 @default.
• W4308385283 creator A5006219407 @default.
• W4308385283 creator A5006822602 @default.
• W4308385283 creator A5008892178 @default.
• W4308385283 creator A5011530260 @default.
• W4308385283 creator A5015722650 @default.
• W4308385283 creator A5017538140 @default.
• W4308385283 creator A5022748925 @default.
• W4308385283 creator A5031953660 @default.
• W4308385283 creator A5044797378 @default.
• W4308385283 creator A5054715840 @default.
• W4308385283 creator A5064342343 @default.
• W4308385283 creator A5074580827 @default.
• W4308385283 creator A5074642572 @default.
• W4308385283 creator A5080859904 @default.
• W4308385283 creator A5086023670 @default.
• W4308385283 creator A5087803810 @default.
• W4308385283 date "2022-11-01" @default.
• W4308385283 modified "2023-10-18" @default.
• W4308385283 title "1081 Exenokine-2: a half-life extended no-α-IL-2 with improved preclinical pharmacological properties supports first-in-human clinical development" @default.
• W4308385283 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1081" @default.
• W4308385283 hasPublicationYear "2022" @default.
• W4308385283 type Work @default.
• W4308385283 citedByCount "0" @default.
• W4308385283 crossrefType "proceedings-article" @default.
• W4308385283 hasAuthorship W4308385283A5005420144 @default.
• W4308385283 hasAuthorship W4308385283A5006219407 @default.
• W4308385283 hasAuthorship W4308385283A5006822602 @default.
• W4308385283 hasAuthorship W4308385283A5008892178 @default.
• W4308385283 hasAuthorship W4308385283A5011530260 @default.
• W4308385283 hasAuthorship W4308385283A5015722650 @default.
• W4308385283 hasAuthorship W4308385283A5017538140 @default.
• W4308385283 hasAuthorship W4308385283A5022748925 @default.
• W4308385283 hasAuthorship W4308385283A5031953660 @default.
• W4308385283 hasAuthorship W4308385283A5044797378 @default.
• W4308385283 hasAuthorship W4308385283A5054715840 @default.
• W4308385283 hasAuthorship W4308385283A5064342343 @default.
• W4308385283 hasAuthorship W4308385283A5074580827 @default.
• W4308385283 hasAuthorship W4308385283A5074642572 @default.
• W4308385283 hasAuthorship W4308385283A5080859904 @default.
• W4308385283 hasAuthorship W4308385283A5086023670 @default.
• W4308385283 hasAuthorship W4308385283A5087803810 @default.
• W4308385283 hasBestOaLocation W43083852831 @default.
• W4308385283 hasConcept C150903083 @default.
• W4308385283 hasConcept C159654299 @default.
• W4308385283 hasConcept C16232356 @default.
• W4308385283 hasConcept C202751555 @default.
• W4308385283 hasConcept C203014093 @default.
• W4308385283 hasConcept C207001950 @default.
• W4308385283 hasConcept C2778690821 @default.
• W4308385283 hasConcept C502942594 @default.
• W4308385283 hasConcept C55493867 @default.
• W4308385283 hasConcept C57992300 @default.
• W4308385283 hasConcept C71924100 @default.
• W4308385283 hasConcept C86803240 @default.
• W4308385283 hasConcept C8891405 @default.
• W4308385283 hasConceptScore W4308385283C150903083 @default.
• W4308385283 hasConceptScore W4308385283C159654299 @default.
• W4308385283 hasConceptScore W4308385283C16232356 @default.
• W4308385283 hasConceptScore W4308385283C202751555 @default.
• W4308385283 hasConceptScore W4308385283C203014093 @default.
• W4308385283 hasConceptScore W4308385283C207001950 @default.
• W4308385283 hasConceptScore W4308385283C2778690821 @default.
• W4308385283 hasConceptScore W4308385283C502942594 @default.
• W4308385283 hasConceptScore W4308385283C55493867 @default.
• W4308385283 hasConceptScore W4308385283C57992300 @default.
• W4308385283 hasConceptScore W4308385283C71924100 @default.
• W4308385283 hasConceptScore W4308385283C86803240 @default.
• W4308385283 hasConceptScore W4308385283C8891405 @default.
• W4308385283 hasLocation W43083852831 @default.
• W4308385283 hasOpenAccess W4308385283 @default.
• W4308385283 hasPrimaryLocation W43083852831 @default.
• W4308385283 hasRelatedWork W2047209980 @default.
• W4308385283 hasRelatedWork W2067960249 @default.
• W4308385283 hasRelatedWork W2119697230 @default.
• W4308385283 hasRelatedWork W2134417758 @default.
• W4308385283 hasRelatedWork W2145306431 @default.
• W4308385283 hasRelatedWork W2297634741 @default.
• W4308385283 hasRelatedWork W2396932951 @default.
• W4308385283 hasRelatedWork W2499862928 @default.
• W4308385283 hasRelatedWork W2800648910 @default.
• W4308385283 hasRelatedWork W2953758866 @default.
• W4308385283 isParatext "false" @default.
• W4308385283 isRetracted "false" @default.
• W4308385283 workType "article" @default.