Matches in SemOpenAlex for { <https://semopenalex.org/work/W4308385286> ?p ?o ?g. }
Showing items 1 to 87 of
87
with 100 items per page.
- W4308385286 abstract "<h3>Background</h3> Despite its potential, the toxicity of interferon alpha has limited its clinical use. CytomX proprietary Probody® Therapeutics (Pb-Tx) technology allowed us to create a conditionally active IFN-a2b (Pb-IFN-a2b) with minimal activity in its prodrug form. The prodrug is activated in the tumor microenvironment (TME), leading to preferential activity in the TME but not in healthy tissues. Pb-IFN-a2b demonstrated a substantially enhanced tolerability profile compared to standard IFN therapy without compromising its antitumor effects. <h3>Methods</h3> The Pb-Tx platform technology attenuates activity of a molecule by blocking its active regions through affinity or steric interference. Such blockade, termed masking, is reversed upon proteolytic cleavage of a linker between the molecule and the mask by tumor associated proteases. <h3>Results</h3> Pb-IFN-a2b demonstrated considerable reduction (1000-fold or more) of interferon signaling in vitro and significantly reduced immune cell activation. Exposure to viable tumor tissues or tumor-associated proteases in vitro fully restored its bioactivity, including the ability of Pb-IFN to stimulate tumor-infiltrating immune cells. Antitumor activity of the Pb-IFN-a2b in xenograft studies is equal to or greater than Peg-IFN-α2b. In syngeneic mouse tumor models, Pb-IFN demonstrated significant antitumor activity that was further enhanced by PD-(L)1 blockade. Activation of lymphocytes by the molecule was observed in tumors but not in secondary lymphoid organs. Toxicology studies performed in hamsters demonstrated enhanced tolerability of the molecule compared to its unmasked control. In addition, Pb-IFN-a2b suppressed growth of hamster melanoma tumor model RPMI1846 at dose levels that were above the tolerated dose of the unmasked control. Biomarkers of IFN signaling were greatly attenuated in non-human primates compared to the unmasked control. In cynomolgus monkey, Pb-IFN-a2b demonstrated linear pharmacokinetics, extended half-life, and was well tolerated at weekly doses up to 60 mg/kg. <h3>Conclusions</h3> Pb-IFN-a2b shows improved tolerability and antitumor activity in preclinical studies compared to traditional IFN treatment. These data support Probody cytokine therapeutics as a promising addition to current immunotherapy regimens, potentially expanding their benefits to patients with typically unresponsive tumors. <h3>Ethics Approval</h3> All animal experiments were reviewed and approved by CytomX’s Institutional Animal Care and Use Committee (IACUC Protocol AP303)." @default.
- W4308385286 created "2022-11-11" @default.
- W4308385286 creator A5005982696 @default.
- W4308385286 creator A5008961682 @default.
- W4308385286 creator A5012245136 @default.
- W4308385286 creator A5012991076 @default.
- W4308385286 creator A5014884453 @default.
- W4308385286 creator A5017079810 @default.
- W4308385286 creator A5018590594 @default.
- W4308385286 creator A5022076310 @default.
- W4308385286 creator A5025139735 @default.
- W4308385286 creator A5036398076 @default.
- W4308385286 creator A5061597203 @default.
- W4308385286 creator A5063657067 @default.
- W4308385286 creator A5064714385 @default.
- W4308385286 creator A5069770767 @default.
- W4308385286 creator A5074642495 @default.
- W4308385286 date "2022-11-01" @default.
- W4308385286 modified "2023-09-25" @default.
- W4308385286 title "1078 Conditionally activatable interferon-alpha 2b improves tolerability and exhibits preferential activity in tumors" @default.
- W4308385286 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1078" @default.
- W4308385286 hasPublicationYear "2022" @default.
- W4308385286 type Work @default.
- W4308385286 citedByCount "0" @default.
- W4308385286 crossrefType "proceedings-article" @default.
- W4308385286 hasAuthorship W4308385286A5005982696 @default.
- W4308385286 hasAuthorship W4308385286A5008961682 @default.
- W4308385286 hasAuthorship W4308385286A5012245136 @default.
- W4308385286 hasAuthorship W4308385286A5012991076 @default.
- W4308385286 hasAuthorship W4308385286A5014884453 @default.
- W4308385286 hasAuthorship W4308385286A5017079810 @default.
- W4308385286 hasAuthorship W4308385286A5018590594 @default.
- W4308385286 hasAuthorship W4308385286A5022076310 @default.
- W4308385286 hasAuthorship W4308385286A5025139735 @default.
- W4308385286 hasAuthorship W4308385286A5036398076 @default.
- W4308385286 hasAuthorship W4308385286A5061597203 @default.
- W4308385286 hasAuthorship W4308385286A5063657067 @default.
- W4308385286 hasAuthorship W4308385286A5064714385 @default.
- W4308385286 hasAuthorship W4308385286A5069770767 @default.
- W4308385286 hasAuthorship W4308385286A5074642495 @default.
- W4308385286 hasBestOaLocation W43083852861 @default.
- W4308385286 hasConcept C108215921 @default.
- W4308385286 hasConcept C181199279 @default.
- W4308385286 hasConcept C182220744 @default.
- W4308385286 hasConcept C185592680 @default.
- W4308385286 hasConcept C197934379 @default.
- W4308385286 hasConcept C202751555 @default.
- W4308385286 hasConcept C203014093 @default.
- W4308385286 hasConcept C2776107976 @default.
- W4308385286 hasConcept C2776178377 @default.
- W4308385286 hasConcept C2778375690 @default.
- W4308385286 hasConcept C502942594 @default.
- W4308385286 hasConcept C55493867 @default.
- W4308385286 hasConcept C71924100 @default.
- W4308385286 hasConcept C8891405 @default.
- W4308385286 hasConcept C98274493 @default.
- W4308385286 hasConceptScore W4308385286C108215921 @default.
- W4308385286 hasConceptScore W4308385286C181199279 @default.
- W4308385286 hasConceptScore W4308385286C182220744 @default.
- W4308385286 hasConceptScore W4308385286C185592680 @default.
- W4308385286 hasConceptScore W4308385286C197934379 @default.
- W4308385286 hasConceptScore W4308385286C202751555 @default.
- W4308385286 hasConceptScore W4308385286C203014093 @default.
- W4308385286 hasConceptScore W4308385286C2776107976 @default.
- W4308385286 hasConceptScore W4308385286C2776178377 @default.
- W4308385286 hasConceptScore W4308385286C2778375690 @default.
- W4308385286 hasConceptScore W4308385286C502942594 @default.
- W4308385286 hasConceptScore W4308385286C55493867 @default.
- W4308385286 hasConceptScore W4308385286C71924100 @default.
- W4308385286 hasConceptScore W4308385286C8891405 @default.
- W4308385286 hasConceptScore W4308385286C98274493 @default.
- W4308385286 hasLocation W43083852861 @default.
- W4308385286 hasOpenAccess W4308385286 @default.
- W4308385286 hasPrimaryLocation W43083852861 @default.
- W4308385286 hasRelatedWork W2035077104 @default.
- W4308385286 hasRelatedWork W2045903301 @default.
- W4308385286 hasRelatedWork W2532815894 @default.
- W4308385286 hasRelatedWork W2765415508 @default.
- W4308385286 hasRelatedWork W2769184973 @default.
- W4308385286 hasRelatedWork W3165143150 @default.
- W4308385286 hasRelatedWork W3206128638 @default.
- W4308385286 hasRelatedWork W4309781227 @default.
- W4308385286 hasRelatedWork W4321478834 @default.
- W4308385286 hasRelatedWork W4361827099 @default.
- W4308385286 isParatext "false" @default.
- W4308385286 isRetracted "false" @default.
- W4308385286 workType "article" @default.