FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308382087> ?p ?o ?g. }

• W4308382087 abstract "<h3>Background</h3> Despite being approved for clinical use over a decade ago, CTLA-4 mAbs remain encumbered by a narrow therapeutic window and relatively severe adverse event (AE) profile. Increasing data support that CTLA-4 mAb efficacy is primarily driven by depletion of CTLA-4+ T regulatory cells (Tregs) in the tumor microenvironment (TME), while AEs have been linked to an overzealous peripheral T cell response mediated by prolonged CTLA-4 blockade. It has been postulated that a more selective approach directly targeting TME-associated Treg cell depletion, while reducing peripheral T cell effects, might improve the tolerability of this class of immune checkpoint inhibitors, yet no CTLA-4 targeted mAb has achieved this. MT-8421 is a potent CTLA-4-targeted engineered toxin body (ETB) that can preferentially deplete high CTLA-4 expressing Tregs in the TME while sparing low CTLA-4 expressing peripheral T cells. In addition, MT-8421 was well-tolerated in a non-GLP non-human primate (NHP) study at doses hundreds-fold higher (450ng/mL) than the IC50 on CTLA-4 expressing cells. Here we demonstrate that MT-8421 synergizes with αPD-1 mAb in a Treg/T cell primary cell co-culture to stimulate T cell proliferative responses through direct Treg cell depletion.¹ Results from animal models including a GLP-NHP study will be described. <h3>Methods</h3> T cells and Tregs were isolated from PBMCs of healthy donors and were stained to track T cell proliferation. T cells were co-cultured with autologous Tregs at various ratios. Anti-CD3/CD28 was used to drive proliferation of T cells in the presence of 4,000ng/mL of MT-8421, inactive MT-8421, or αPD-1 mAb (20µg/mL) to test for monotherapy activity. In addition, cells were treated with αPD-1 mAb followed by MT-8421 to evaluate combination effects. After 4 days, cells were stained with surface antibodies and analyzed by flow cytometry. <h3>Results</h3> Co-cultures treated with MT-8421 alone demonstrated release of Treg-mediated CD8 T cell suppression compared to the untreated or inactive MT-8421. In addition, while αPD-1 treatment alone expectedly increased CD4+ and CD8+ T cell proliferation, when followed by MT-8421 treatment, the effects on T cell proliferation were greater than with either treatment alone. <h3>Conclusions</h3> MT-8421 is a novel approach to CTLA-4 targeting: a potent depletion of TME CTLA-4+ Tregs without long-lasting CTLA-4 blockade in the periphery. This approach may allow for enhanced efficacy over current antibody approaches through the elimination of Tregs in the TME. The lack of prolonged peripheral CTLA-4 blockade may reduce toxicity as seen with antibody approaches to CTLA-4. Clinical studies are expected to start in 2023. <h3>Reference</h3> Sarkar A, Martin R, Byrne LR, Howard C, Khanna S, Rabia LA, Adhikari D, Sousares MM, Aldana A, Robinson GL, Zhao J, Moore CB, Iberg A. A CTLA-4 targeted ETB for Treg depletion shows favorable preclinical efficacy and safety. <i>Cancer Research</i> 2022; <b>82</b>:12 supplement, 3538–3538." @default.
• W4308382087 created "2022-11-11" @default.
• W4308382087 creator A5000342928 @default.
• W4308382087 creator A5009418303 @default.
• W4308382087 creator A5022163485 @default.
• W4308382087 creator A5028236397 @default.
• W4308382087 creator A5042459510 @default.
• W4308382087 creator A5044593776 @default.
• W4308382087 creator A5054950406 @default.
• W4308382087 creator A5069638122 @default.
• W4308382087 creator A5088989273 @default.
• W4308382087 creator A5089458443 @default.
• W4308382087 date "2022-11-01" @default.
• W4308382087 modified "2023-09-25" @default.
• W4308382087 title "817 Engineered toxin body targeting CTLA-4 (MT-8421) depletes Tregs in the tumor microenvironment and synergizes with αPD-1 to enhance T cell immunity" @default.
• W4308382087 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0817" @default.
• W4308382087 hasPublicationYear "2022" @default.
• W4308382087 type Work @default.
• W4308382087 citedByCount "0" @default.
• W4308382087 crossrefType "proceedings-article" @default.
• W4308382087 hasAuthorship W4308382087A5000342928 @default.
• W4308382087 hasAuthorship W4308382087A5009418303 @default.
• W4308382087 hasAuthorship W4308382087A5022163485 @default.
• W4308382087 hasAuthorship W4308382087A5028236397 @default.
• W4308382087 hasAuthorship W4308382087A5042459510 @default.
• W4308382087 hasAuthorship W4308382087A5044593776 @default.
• W4308382087 hasAuthorship W4308382087A5054950406 @default.
• W4308382087 hasAuthorship W4308382087A5069638122 @default.
• W4308382087 hasAuthorship W4308382087A5088989273 @default.
• W4308382087 hasAuthorship W4308382087A5089458443 @default.
• W4308382087 hasBestOaLocation W43083820871 @default.
• W4308382087 hasConcept C203014093 @default.
• W4308382087 hasConcept C21705690 @default.
• W4308382087 hasConcept C2776090121 @default.
• W4308382087 hasConcept C2776107976 @default.
• W4308382087 hasConcept C502942594 @default.
• W4308382087 hasConcept C71924100 @default.
• W4308382087 hasConcept C86803240 @default.
• W4308382087 hasConcept C8891405 @default.
• W4308382087 hasConceptScore W4308382087C203014093 @default.
• W4308382087 hasConceptScore W4308382087C21705690 @default.
• W4308382087 hasConceptScore W4308382087C2776090121 @default.
• W4308382087 hasConceptScore W4308382087C2776107976 @default.
• W4308382087 hasConceptScore W4308382087C502942594 @default.
• W4308382087 hasConceptScore W4308382087C71924100 @default.
• W4308382087 hasConceptScore W4308382087C86803240 @default.
• W4308382087 hasConceptScore W4308382087C8891405 @default.
• W4308382087 hasLocation W43083820871 @default.
• W4308382087 hasOpenAccess W4308382087 @default.
• W4308382087 hasPrimaryLocation W43083820871 @default.
• W4308382087 hasRelatedWork W1988241479 @default.
• W4308382087 hasRelatedWork W2079632471 @default.
• W4308382087 hasRelatedWork W2322919275 @default.
• W4308382087 hasRelatedWork W2950289579 @default.
• W4308382087 hasRelatedWork W2978160979 @default.
• W4308382087 hasRelatedWork W2987238277 @default.
• W4308382087 hasRelatedWork W3031104395 @default.
• W4308382087 hasRelatedWork W3039388108 @default.
• W4308382087 hasRelatedWork W3165724578 @default.
• W4308382087 hasRelatedWork W4327715451 @default.
• W4308382087 isParatext "false" @default.
• W4308382087 isRetracted "false" @default.
• W4308382087 workType "article" @default.