title: SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression.
abstract: Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide-based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900-9. ©2016 AACR.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Gulden
authors.initials: G
authors.lastname: Menderes
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Carlton L
authors.initials: CL
authors.lastname: Schwab
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonazzoli
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Federica
authors.initials: F
authors.lastname: Predolini
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Christopher
authors.initials: C
authors.lastname: De Haydu
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Pei
authors.initials: P
authors.lastname: Hui
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Serena
authors.initials: S
authors.lastname: Wong
authors.affiliation: Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lopez
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Elena
authors.initials: E
authors.lastname: Ratner
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Dan-Arin
authors.initials: DA
authors.lastname: Silasi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Babak
authors.initials: B
authors.lastname: Litkouhi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.affiliation: Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Goedings
authors.affiliation: Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Beusker
authors.affiliation: Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
authors.forename: Miranda M C
authors.initials: MM
authors.lastname: van der Lee
authors.affiliation: Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
authors.forename: C Marco
authors.initials: CM
authors.lastname: Timmers
authors.affiliation: Synthon Biopharmaceuticals BV., Nijmegen, the Netherlands.
authors.forename: Wim H A
authors.initials: WH
authors.lastname: Dokter
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut. alessandro.santin@yale.edu.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D024201:Bystander Effect; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000080890:Duocarmycins; D005260:Female; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002401:Cathepsin B; D058534:Class I Phosphatidylinositol 3-Kinases; D000080890:Duocarmycins; D018796:Immunoconjugates; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D011760:Pyrrolidinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C484760:PIK3CA protein, human; C058289:duocarmycin A