RT Journal Article
SR Electronic
T1 In Vivo Characterization of Platinum(II)-Based Linker Technology for the Development of Antibody–Drug Conjugates: Taking Advantage of Dual Labeling with <sup>195m</sup>Pt and <sup>89</sup>Zr
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1146
OP 1151
DO 10.2967/jnumed.117.206672
VO 59
IS 7
A1 Muns, Joey A.
A1 Montserrat, Veronica
A1 Houthoff, Hendrik-Jan
A1 Codée-van der Schilden, Karlijn
A1 Zwaagstra, Oene
A1 Sijbrandi, Niels J.
A1 Merkul, Eugen
A1 van Dongen, Guus A.M.S.
YR 2018
UL http://jnm.snmjournals.org/content/59/7/1146.abstract
AB 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]Lx. 89Zr-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 (DARs) of 2.2–2.5. To assess the influence of DAR on biodistribution, 89Zr-DFO-(Lys)trastuzumab-Lx-AF with an AF-to-antibody ratio of 0, 2.6, or 5.2 was evaluated 96 h after injection. Results: Similar biodistributions were observed for trastuzumab-[195mPt]Lx-DFO-89Zr, trastuzumab-[195mPt]Lx-AF, and 89Zr-DFO-(Lys)trastuzumab irrespective of the isotope used for biodistribution assessment. The fact that Lx follows the antibody biodistribution indicates that the payload-Lx bond is stable in vivo. Uptake of the 3 conjugates, as percentage injected dose (%ID) per gram of tissue, was about 30 %ID/g in tumor tissue but less than 10 %ID/g in most healthy tissues. Trastuzumab-[195mPt]Lx-AF (DAR 2.2) showed a tendency toward faster blood clearance and an elevated liver uptake, which increased significantly to 28.1 ± 4.2 %ID/g at a higher DAR of 5.2, as revealed from the biodistribution and PET imaging studies. Conclusion: As shown by 195mPt/89Zr labeling, ADCs containing the Lx linker are stable in vivo. In the case of trastuzumab-Lx-AF (DARs 2.2 and 2.6), an unimpaired biodistribution was demonstrated.