ChAcNLS-A14, a novel antibody-conjugate PET tracer for targeting human IL-5Rα-positive muscle invasive bladder cancer
Notice bibliographique
Résumé
52 Objectives 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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».