title: Preclinical profile of the HER2-targeting ADC SYD983/SYD985: introduction of a new duocarmycin-based linker-drug platform.
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. The ADC is 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.
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands. Wim.Dokter@synthon.com.
authors.forename: Wim
authors.initials: W
authors.lastname: Dokter
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Ubink
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: van der Lee
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: van der Vleuten
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Tanja
authors.initials: T
authors.lastname: van Achterberg
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Jacobs
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Eline
authors.initials: E
authors.lastname: Loosveld
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Diels
authors.initials: D
authors.lastname: van den Dobbelsteen
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Egging
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Mattaar
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Groothuis
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Beusker
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Coumans
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Elgersma
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Wiro
authors.initials: W
authors.lastname: Menge
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Joosten
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Henri
authors.initials: H
authors.lastname: Spijker
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Tijl
authors.initials: T
authors.lastname: Huijbregts
authors.affiliation: Department of Antibody-Drug Conjugates, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: de Groot
authors.affiliation: Department of Downstream Processing, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Michel
authors.initials: M
authors.lastname: Eppink
authors.affiliation: Department of Downstream Processing, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Guy
authors.initials: G
authors.lastname: de Roo
authors.affiliation: Department of New Molecular Entities, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: Verheijden
authors.affiliation: Department of New Molecular Entities, Synthon Biopharmaceuticals BV, Nijmegen, the Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Timmers
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000737:chemistry; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000080890:Duocarmycins; D000922:Immunotoxins; D007211:Indoles; D011760:Pyrrolidinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C058289:duocarmycin A