RT Journal Article
SR Electronic
T1 ChAcNLS-A14, a novel antibody-conjugate PET tracer for targeting human IL-5Rα-positive muscle invasive bladder cancer
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 52
OP 52
VO 57
IS supplement 2
A1 Paquette, Michel
A1 Beaudoin, Simon
A1 Fafard-Couture, Laurent
A1 Vilera-Perez, Luis-Guillermo
A1 Ekindi-Ndongo, Nadia
A1 Lopez, Angel
A1 Lecomte, Roger
A1 Sabbagh, Robert
A1 Guerin, Brigitte
A1 Leyton, Jeff
YR 2016
UL http://jnm.snmjournals.org/content/57/supplement_2/52.abstract
AB 52Objectives Recently, it has been reported that Interleukin-5-receptor (IL-5R) is implicated in tumor invasiveness in muscle invasive bladder cancer (MIBC). A cholic acid coupled to a Nuclear Localisation Signal peptide (ChAcNLS) is a novel technology developed for increased intracellular accumulation of targeted chemotherapies with antibody-drug conjugates (ADCs). ChAcNLS-conjugated antibodies use an alternative strategy, contrary to the standard intracellular delivery approach which relies on ADC degradation via the endosomal-lysosomal pathway and drug release within the target cell. ChAcNLS enables ADCs to evade lysosome degradation by escaping endosome entrapment and redirecting their trafficking to the nucleus. This results in increased intracellular accumulation. The aim of this study was to evaluate if the functionalization of the monoclonal antibody (mAb) A14 with ChAcNLS could improve tumor accumulation of the positron emitter 64Cu in xenografts of IL-5R-positive MIBC and to assess its potential as a PET tracer for MIBC imaging. The in vivo pharmacokinetic and tumor-targeting properties of [64Cu]-A14-ChAcNLS was compared to [64Cu]-A14 in MIBC-tumor bearing mice by positron emission tomography (PET) imaging and biodistribution.Methods A14 was conjugated with the copper chelator NOTA, then further conjugated to ChAcNLS moieties. Labeling yielded a specific activity of 250 MBq/mg. NOD/SCID mice were implanted subcutaneously with 5×106 HT1376 (high IL-5R expression) and HTB9 (low IL-5R expression) human MIBC cells on separate flanks. When tumors reached >4 mm diameter, mice were injected with 25 µg (≍6 MBq) of [64Cu]-A14 or [64Cu]-A14-ChAcNLS followed by daily PET imaging, up to 72 h post-injection. Biodistribution was performed at 48 h and 96 h post-injection. Specific binding to the tumors was assessed by injection of 25 mg/kg unlabeled A14 24 h prior to tracer injection, followed by imaging and dissection at 48 h post-injection. Dissection and PET data were used to compare the in vivo uptake (%ID/g) of MIBC tumors relative to healthy organs.Results Increased radioactive uptake in HT1376 tumors relative to HTB9 tumors was observed at all time points using both ACs, which was consistent with their relative IL-5R expression levels. There was a significantly lower blood pool, along with lower muscle uptake when [64Cu]-ChAcNLS-A14 was used compared to 64Cu-A14. Higher kidney uptake was observed using [64Cu]-ChAcNLS-A14 compared to [64Cu]-A14. No bladder uptake could be detected in PET images. Tumors showed similar uptake for both tracers, and pre-injection of a blocking dose of A14 resulted in a ≍50% drop of uptake, assessed by both PET and biodistribution. Thanks to decreased background, tumor-to-muscle and tumor-to-blood ratios were improved with [64Cu]-A14-ChAcNLS, resulting in better specific targeting of MIBC tumors than with [64Cu]-A14.Conclusions A14-ChAcNLS exhibited improved pharmacokinetics resulting in enhanced tumor-specific targeting. A14-ChAcNLS displays suitable in vivo properties to proceed to IL-5Rα PET imaging of human MIBC.