Matches in SemOpenAlex for { <https://semopenalex.org/work/W4362541771> ?p ?o ?g. }
Showing items 1 to 100 of
100
with 100 items per page.
- W4362541771 abstract "<div>Abstract<p>Carboxylesterase 1c (CES1c) is responsible for linker-drug instability and poor pharmacokinetics (PK) of several antibody–drug conjugates (ADC) in mice, but not in monkeys or humans. Preclinical development of these ADCs could be improved if the PK in mice would more closely resemble that of humans and is not affected by an enzyme that is irrelevant for humans. SYD985, a HER2-targeting ADC based on trastuzumab and linker-drug vc-<i>seco</i>-DUBA, is also sensitive to CES1c. In the present studies, we first focused on the interaction between CES1c and SYD985 by size- exclusion chromatography, Western blotting, and LC/MS-MS analysis, using recombinant CES1c and plasma samples. Intriguingly, CES1c activity not only results in release of the active toxin DUBA but also in formation of a covalent bond between CES1c and the linker of vc-<i>seco</i>-DUBA. Mass spectrometric studies enabled identification of the CES1c cleavage site on the linker-drug and the structure of the CES1c adduct. To assess the <i>in vivo</i> impact, CES1c<sup>−/−</sup> SCID mice were generated that showed stable PK for SYD985, comparable to that in monkeys and humans. Patient-derived xenograft (PDX) studies in these mice showed enhanced efficacy compared with PDX studies in CES1c<sup>+/+</sup> mice and provided a more accurate prediction of clinical efficacy of SYD985, hence delivering better quality data. It seems reasonable to assume that CES1c<sup>−/−</sup> SCID mice can increase quality in ADC development much broader for all ADCs that carry linker-drugs susceptible to CES1c, without the need of chemically modifying the linker-drug to specifically increase PK in mice. <i>Mol Cancer Ther; 17(11); 2389–98. ©2018 AACR</i>.</p></div>" @default.
- W4362541771 created "2023-04-06" @default.
- W4362541771 creator A5002534856 @default.
- W4362541771 creator A5006427874 @default.
- W4362541771 creator A5008878560 @default.
- W4362541771 creator A5045049392 @default.
- W4362541771 creator A5045671996 @default.
- W4362541771 creator A5048654956 @default.
- W4362541771 creator A5060268565 @default.
- W4362541771 creator A5060668833 @default.
- W4362541771 creator A5066695787 @default.
- W4362541771 creator A5071373994 @default.
- W4362541771 creator A5075438722 @default.
- W4362541771 creator A5083069711 @default.
- W4362541771 creator A5087092324 @default.
- W4362541771 creator A5087798064 @default.
- W4362541771 creator A5089396219 @default.
- W4362541771 date "2023-04-03" @default.
- W4362541771 modified "2023-10-18" @default.
- W4362541771 title "Data from Unraveling the Interaction between Carboxylesterase 1c and the Antibody–Drug Conjugate SYD985: Improved Translational PK/PD by Using Ces1c Knockout Mice" @default.
- W4362541771 doi "https://doi.org/10.1158/1535-7163.c.6537982.v1" @default.
- W4362541771 hasPublicationYear "2023" @default.
- W4362541771 type Work @default.
- W4362541771 citedByCount "0" @default.
- W4362541771 crossrefType "posted-content" @default.
- W4362541771 hasAuthorship W4362541771A5002534856 @default.
- W4362541771 hasAuthorship W4362541771A5006427874 @default.
- W4362541771 hasAuthorship W4362541771A5008878560 @default.
- W4362541771 hasAuthorship W4362541771A5045049392 @default.
- W4362541771 hasAuthorship W4362541771A5045671996 @default.
- W4362541771 hasAuthorship W4362541771A5048654956 @default.
- W4362541771 hasAuthorship W4362541771A5060268565 @default.
- W4362541771 hasAuthorship W4362541771A5060668833 @default.
- W4362541771 hasAuthorship W4362541771A5066695787 @default.
- W4362541771 hasAuthorship W4362541771A5071373994 @default.
- W4362541771 hasAuthorship W4362541771A5075438722 @default.
- W4362541771 hasAuthorship W4362541771A5083069711 @default.
- W4362541771 hasAuthorship W4362541771A5087092324 @default.
- W4362541771 hasAuthorship W4362541771A5087798064 @default.
- W4362541771 hasAuthorship W4362541771A5089396219 @default.
- W4362541771 hasBestOaLocation W43625417712 @default.
- W4362541771 hasConcept C111919701 @default.
- W4362541771 hasConcept C112705442 @default.
- W4362541771 hasConcept C134306372 @default.
- W4362541771 hasConcept C150903083 @default.
- W4362541771 hasConcept C153911025 @default.
- W4362541771 hasConcept C159654299 @default.
- W4362541771 hasConcept C181199279 @default.
- W4362541771 hasConcept C185592680 @default.
- W4362541771 hasConcept C197336794 @default.
- W4362541771 hasConcept C203014093 @default.
- W4362541771 hasConcept C207001950 @default.
- W4362541771 hasConcept C2777325958 @default.
- W4362541771 hasConcept C2778325069 @default.
- W4362541771 hasConcept C2780035454 @default.
- W4362541771 hasConcept C2780557392 @default.
- W4362541771 hasConcept C33923547 @default.
- W4362541771 hasConcept C41008148 @default.
- W4362541771 hasConcept C542903549 @default.
- W4362541771 hasConcept C55493867 @default.
- W4362541771 hasConcept C86803240 @default.
- W4362541771 hasConcept C98274493 @default.
- W4362541771 hasConceptScore W4362541771C111919701 @default.
- W4362541771 hasConceptScore W4362541771C112705442 @default.
- W4362541771 hasConceptScore W4362541771C134306372 @default.
- W4362541771 hasConceptScore W4362541771C150903083 @default.
- W4362541771 hasConceptScore W4362541771C153911025 @default.
- W4362541771 hasConceptScore W4362541771C159654299 @default.
- W4362541771 hasConceptScore W4362541771C181199279 @default.
- W4362541771 hasConceptScore W4362541771C185592680 @default.
- W4362541771 hasConceptScore W4362541771C197336794 @default.
- W4362541771 hasConceptScore W4362541771C203014093 @default.
- W4362541771 hasConceptScore W4362541771C207001950 @default.
- W4362541771 hasConceptScore W4362541771C2777325958 @default.
- W4362541771 hasConceptScore W4362541771C2778325069 @default.
- W4362541771 hasConceptScore W4362541771C2780035454 @default.
- W4362541771 hasConceptScore W4362541771C2780557392 @default.
- W4362541771 hasConceptScore W4362541771C33923547 @default.
- W4362541771 hasConceptScore W4362541771C41008148 @default.
- W4362541771 hasConceptScore W4362541771C542903549 @default.
- W4362541771 hasConceptScore W4362541771C55493867 @default.
- W4362541771 hasConceptScore W4362541771C86803240 @default.
- W4362541771 hasConceptScore W4362541771C98274493 @default.
- W4362541771 hasLocation W43625417711 @default.
- W4362541771 hasLocation W43625417712 @default.
- W4362541771 hasOpenAccess W4362541771 @default.
- W4362541771 hasPrimaryLocation W43625417711 @default.
- W4362541771 hasRelatedWork W1491964893 @default.
- W4362541771 hasRelatedWork W2004556784 @default.
- W4362541771 hasRelatedWork W2379311614 @default.
- W4362541771 hasRelatedWork W2388069209 @default.
- W4362541771 hasRelatedWork W2461520869 @default.
- W4362541771 hasRelatedWork W2582907174 @default.
- W4362541771 hasRelatedWork W2753834235 @default.
- W4362541771 hasRelatedWork W2772480130 @default.
- W4362541771 hasRelatedWork W4214766446 @default.
- W4362541771 hasRelatedWork W4239568381 @default.
- W4362541771 isParatext "false" @default.
- W4362541771 isRetracted "false" @default.
- W4362541771 workType "article" @default.