title: A Novel Platinum(II)-Based Bifunctional ADC Linker Benchmarked Using 89Zr-Desferal and Auristatin F-Conjugated Trastuzumab.
abstract: Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable "semifinal" products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85% payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with89Zr. Trastuzumab-Lx-DFO-89Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs. Cancer Res; 77(2); 257-67. ©2016 AACR.
authors.affiliation: LinXis B.V., Amsterdam, the Netherlands. sijbrandi@linxispharmaceuticals.com.
authors.forename: Niels J
authors.initials: NJ
authors.lastname: Sijbrandi
authors.affiliation: LinXis B.V., Amsterdam, the Netherlands.
authors.forename: Eugen
authors.initials: E
authors.lastname: Merkul
authors.affiliation: LinXis B.V., Amsterdam, the Netherlands.
authors.forename: Joey A
authors.initials: JA
authors.lastname: Muns
authors.affiliation: Department of Radiology and Nuclear Medicine, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Dennis C J
authors.initials: DC
authors.lastname: Waalboer
authors.affiliation: Department of Radiology and Nuclear Medicine, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Kevin
authors.initials: K
authors.lastname: Adamzek
authors.affiliation: Department of Radiology and Nuclear Medicine, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Bolijn
authors.affiliation: LinXis B.V., Amsterdam, the Netherlands.
authors.forename: Veronica
authors.initials: V
authors.lastname: Montserrat
authors.affiliation: Division of BioAnalytical Chemistry, AIMMS Research Group BioMolecular Analysis, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
authors.forename: Govert W
authors.initials: GW
authors.lastname: Somsen
authors.affiliation: Division of BioAnalytical Chemistry, AIMMS Research Group BioMolecular Analysis, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Haselberg
authors.affiliation: LinXis B.V., Amsterdam, the Netherlands.
authors.forename: Paul J G M
authors.initials: PJ
authors.lastname: Steverink
authors.affiliation: LinXis B.V., Amsterdam, the Netherlands.
authors.forename: Hendrik-Jan
authors.initials: HJ
authors.lastname: Houthoff
authors.affiliation: Department of Radiology and Nuclear Medicine, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Guus A M S
authors.initials: GA
authors.lastname: van Dongen
mesh_terms: D062365:Aminobenzoates; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003676:Deferoxamine; D015195:Drug Design; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D009842:Oligopeptides; D017671:Platinum Compounds; D011849:Radioactive Tracers; D013274:Stomach Neoplasms / Q000473:pathology; D000068878:Trastuzumab / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009842:Oligopeptides; D017671:Platinum Compounds; D011849:Radioactive Tracers; C543533:auristatin; D015040:Zirconium; D003676:Deferoxamine; D000068878:Trastuzumab