Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 483582
Title Preclinical Profile of the HER2-Targeting ADC SYD983/SYD985: Introduction of a New Duocarmycin-Based Linker-Drug Platform
Author(s) Dokter, W.; Ubink, R.; Lee, M. van der; Vleuten, M. van der; Achterberg, T. van; Jacobs, D.; Loosveld, E.; Dobbelsteen, D. van den; Egging, D.; Mattaar, E.; Groothuis, P.; Beusker, P.; Coumans, R.; Elgersma, R.; Menge, W.; Joosten, J.; Spijker, H.; Huijbregts, T.; Groot, V. de; Eppink, M.H.M.; Roo, G. de; Verheijden, G.; Timmers, M.
Source Molecular Cancer Therapeutics 13 (2014). - ISSN 1535-7163 - p. 2618 - 2629.
DOI https://doi.org/10.1158/1535-7163.MCT-14-0040-T
Department(s) Bioprocess Engineering
VLAG
Publication type Refereed Article in a scientific journal
Publication year 2014
Keyword(s) metastatic breast-cancer - growth-factor receptor - phase-ii - trastuzumab emtansine - brentuximab vedotin - cathepsin-b - human pharmacokinetics - monoclonal-antibody - malignant-melanoma - antitumor-activity
Abstract A linker-drug platform was built on the basis of a cleavable linker-duocarmycin payload for the development of new-generation antibody–drug conjugates (ADC). A leading ADC originating from that platform is SYD983, a HER2-targeting ADC based on trastuzumab. HER2-binding, antibody-dependent cell-mediated cytotoxicity and HER2-mediated internalization are similar for SYD983 as compared with trastuzumab. HER2- expressing cells in vitro are very potently killed by SYD983, but SYD983 is inactive in cells that do not express HER2. SYD983 dose dependently reduces tumor growth in a BT-474 mouse xenograft in vivo. TheADCis stable in human and cynomolgus monkey plasma in vitro but shows relatively poor stability in mouse plasma due to mouse-specific carboxylesterase. SYD983 could be dosed up to 30 mg/kg in cynomolgus monkeys with high exposure, excellent stability in blood, and without severe toxic effects. The monkey safety study showed no SYD983-induced thrombocytopenia and no induction of peripheral sensory neuropathy, both commonly observed in trials and studies with ADCs based on tubulin inhibitors. Finally, to improve homogeneity, SYD983 was further purified by hydrophobic interaction chromatography resulting in an ADC (designated SYD985) predominantly containing DAR2 and DAR4 species. SYD985 showed high antitumor activity in two patient-derived xenograft models of HER2-positive metastatic breast cancers. In conclusion, the data obtained indicate great potential for this new HER2-targeting ADC to become an effective drug for patients with HER2- positive cancers with a favorable safety profile. More generally, this new-generation duocarmycin-based linker-drug technology could be used with other mAbs to serve more indications in oncology.
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