In Vivo Characterization of Platinum(II)-Based Linker Technology for the Development of Antibody-Drug Conjugates: Taking Advantage of Dual Labeling with 195m Pt and 89 Zr

Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine
Joey A MunsGuus A M S van Dongen

Abstract

Linker instability and impaired tumor targeting can affect the tolerability and efficacy of antibody-drug conjugates (ADCs). To improve these ADC characteristics, we recently described the use of a metal-organic linker, [ethylenediamineplatinum(II)]2+, herein called Lx Initial therapy studies in xenograft-bearing mice revealed that trastuzumab-Lx-auristatin F (AF) outperformed its maleimide benchmark trastuzumab-mal-AF and the Food and Drug Administration-approved ado-trastuzumab emtansine, both containing conventional linkers. In this study, we aimed to characterize Lx-based ADCs for in vivo stability and tumor targeting using 195mPt and 89Zr. Methods: The γ-emitter 195mPt was used to produce the radiolabeled Lx [195mPt]Lx89Zr-Desferrioxamine (89Zr-DFO) was conjugated to trastuzumab either via [195mPt]Lx (to histidine residues) or conventionally (to lysine residues) in order to monitor the biodistribution of antibody, payload, and linker separately. Linker stability was determined by evaluating the following ADCs for biodistribution in NCI-N87 xenograft-bearing nude mice 72 h after injection: trastuzumab-[195mPt]Lx-DFO-89Zr, trastuzumab-[195mPt]Lx-AF, and 89Zr-DFO-(Lys)trastuzumab (control), all having drug-to-antibody ratios ...Continue Reading

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Citations

Oct 30, 2018·Molecular Imaging·Kendra S Carmon, Ali Azhdarinia
Dec 18, 2020·Pharmaceuticals·Héloïse Cahuzac, Laurent Devel
Dec 6, 2020·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Guus A M S van DongenDanielle J Vugts
Jun 15, 2021·Chemical Science·Elizabeth J AnthonyZijin Zhang
Mar 24, 2020·Chemical Reviews·Weijun WeiWeibo Cai
Apr 4, 2020·Bioconjugate Chemistry·Samuel M Meier-Menches, Angela Casini
Aug 23, 2019·Journal of Inorganic Biochemistry·Virginia Del Solar, María Contel

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