ChAcNLS-A14, a novel antibody-conjugate PET tracer for targeting human IL-5Rα-positive muscle invasive bladder cancer
Bibliographic record
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".