title: Preclinical Efficacy of the Auristatin-Based Antibody-Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors.
abstract: The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody-drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line-based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated. Cancer Res; 76(21); 6331-9. ©2016 AACR.
authors.affiliation: Bayer Pharma AG, Berlin, Germany. anette.sommer@bayer.com.
authors.forename: Anette
authors.initials: A
authors.lastname: Sommer
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kopitz
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Schatz
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Nising
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mahlert
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Lerchen
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Stelte-Ludwig
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hammer
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Greven
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schuhmacher
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Braun
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Zierz
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wittemer-Rump
authors.affiliation: Bayer Intellectual Property GmbH, Monheim, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Harrenga
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dittmer
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Reetz
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Apeler
authors.affiliation: Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jautelat
authors.affiliation: National Cancer Center Singapore, Division of Cellular & Molecular Research, Singapore.
authors.forename: Hung
authors.initials: H
authors.lastname: Huynh
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
authors.affiliation: Bayer Pharma AG, Berlin, Germany.
authors.forename: Bertolt
authors.initials: B
authors.lastname: Kreft
mesh_terms: D062365:Aminobenzoates / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000032:analysis* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D009842:Oligopeptides; C543533:auristatin; C000621819:aprutumab ixadotin; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2