A Novel Platinum(II)-Based Bifunctional ADC Linker Benchmarked Using Zr-89-Desferal and Auristatin F-Conjugated Trastuzumab

Niels J. Sijbrandi, Eugen Merkul, Joey A. Muns, Dennis C. J. Waalboer, Kevin Adamzek, Marije Bolijn, Veronica Montserrat, Govert W. Somsen, Rob Haselberg, Paul J. G. M. Steverink, Hendrik-Jan Houthoff, Guus A. M. S. van Dongen

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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 with 89Zr. Trastuzumab-Lx-DFO-98Zr 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.

Original languageEnglish
Pages (from-to)257-267
Number of pages11
JournalCancer research
Issue number2
Publication statusPublished - 15 Jan 2017

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