title: The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers.
abstract: SYD985 is a HER2-targeting antibody-drug conjugate (ADC) based on trastuzumab and vc-seco-DUBA, a cleavable linker-duocarmycin payload. To evaluate the therapeutic potential of this new ADC, mechanistic in vitro studies and in vivo patient-derived xenograft (PDX) studies were conducted to compare SYD985 head-to-head with T-DM1 (Kadcyla), another trastuzumab-based ADC. SYD985 and T-DM1 had similar binding affinities to HER2 and showed similar internalization. In vitro cytotoxicity assays showed similar potencies and efficacies in HER2 3+ cell lines, but in cell lines with low HER2 expression, SYD985 was 3- to 50-fold more potent than T-DM1. In contrast with T-DM1, SYD985 efficiently induced bystander killing in vitro in HER2-negative (HER2 0) cells mixed with HER2 3+, 2+, or 1+ cell lines. At pH conditions relevant for tumors, cathepsin-B cleavage studies showed efficient release of the active toxin by SYD985 but not by T-DM1. These in vitro data suggest that SYD985 might be a more potent ADC in HER2-expressing tumors in vivo, especially in low HER2-expressing and/or in heterogeneous tumors. In line with this, in vivo antitumor studies in breast cancer PDX models showed that SYD985 is very active in HER2 3+, 2+, and 1+ models, whereas T-DM1 only showed significant antitumor activity in HER2 3+ breast cancer PDX models. These properties of SYD985 may enable expansion of the target population to patients who have low HER2-expressing breast cancer, a patient population with still unmet high medical need.
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Miranda M C
authors.initials: MM
authors.lastname: van der Lee
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Groothuis
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Ubink
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Monique A J
authors.initials: MA
authors.lastname: van der Vleuten
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: van Achterberg
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Eline M
authors.initials: EM
authors.lastname: Loosveld
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Désirée
authors.initials: D
authors.lastname: Damming
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Daniëlle C H
authors.initials: DC
authors.lastname: Jacobs
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Myrthe
authors.initials: M
authors.lastname: Rouwette
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: David F
authors.initials: DF
authors.lastname: Egging
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Diels
authors.initials: D
authors.lastname: van den Dobbelsteen
authors.affiliation: Department of Medicinal and Protein Chemistry, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Beusker
authors.affiliation: Department of Medical R&D, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Goedings
authors.affiliation: Department of New Molecular Entities, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Gijs F M
authors.initials: GF
authors.lastname: Verheijden
authors.affiliation: Department of New Molecular Entities, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Jacques M
authors.initials: JM
authors.lastname: Lemmens
authors.affiliation: Department of New Molecular Entities, Synthon Biopharmaceuticals, Nijmegen, the Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Timmers
authors.affiliation: Department of Preclinical, Synthon Biopharmaceuticals, Nijmegen, the Netherlands. Wim.Dokter@Synthon.Com.
authors.forename: Wim H A
authors.initials: WH
authors.lastname: Dokter
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D000080890:Duocarmycins; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011760:Pyrrolidinones / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000080890:Duocarmycins; D007211:Indoles; D011760:Pyrrolidinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C058289:duocarmycin A