PET imaging cancer stem cells using a novel zirconium-89 labelled fully human anti-CD133 antibody
Bibliographic record
Abstract
154 Introduction: Cancer stem cells (CSCs) identified by the CD133 antigen constitute a treatment refractory tumor subpopulation liable to repopulate tumors following therapy. We present [89Zr]Zr-DFO-RW03, a PET imaging probe for CD133 consisting of a novel fully human antibody labelled with long lived positron emitting radioisotope ziconium-89, for use in diagnostic imaging and as a companion diagnostic to cancer stem cell targeted therapy. The stable and highly pure radiolabeled conjugate shows affinity to CD133 in vitro, and in vivo biodistribution and imaging studies demonstrate receptor mediated uptake for tumor delineation in a xenograft mouse model. Methods: We used a robust conjugation strategy to attach 3 molar equivalents of bifunctional chelator DFO-Bn-NCS to RW03 and radiolabeled the DFO-RW03 conjugate with [89Zr]Zr-oxalate to yield [89Zr]Zr-DFO-RW03. The radiolabeled product was incubated, in increasing concentrations, with CD133 expressing HT-29 cells to determine the KD by fitting with a one-site binding curve. In vivo, BALB/c nu/nu mice bearing HT-29 xenografts were injected with 0.185 MBq (2 µg) of [89Zr]Zr-DFO-RW03 and sacrificed after 24, 48, 96 h for organ collection and gamma counting. In a second study, tumor bearing mice were injected with 0.185 MBq (2 µg) of [89Zr]Zr-DFO-RW03 and a 250x mass excess (500 µg) cold antibody block, followed by sacrifice after 96 h and organ counting. For PET imaging, HT-29 bearing mice were injected with 5.5 MBq (35 µg) [89Zr]Zr-DFO-RW03 and imaged over 1 week. ROIs were selected and compared to ex vivo biodistribution, while intratumoral heterogeneity and tumor to muscle ratio was further established using autoradiography. Results: Radiolabeled [89Zr]Zr-DFO-RW03 had high specific activity (>148 MBq/mg) with >99% radiochemical purity, while retaining high affinity for CD133 (KD 15 %ID/g after 96 h with high tumor-to-blood ratio (>5:1) and low bone uptake ( 6:1). Conclusions: Novel CD133 targeted PET imaging probe [89Zr]Zr-DFO-RW03 was syntheized with high specific activty and radiochemical purity and demonstrated CD133 binding both in vitro and in vivo using the model CD133 expressing HT-29 cell line. Tumor uptake was specific for CD133 and heterogenous within the tumor, particularly high in the tumor core, and offering good contrast with background tissue. The probe represents a promising candidate for diagnostic imaging or companion diagnostics in the clinic. Acknowledgements: Support for this work includes OICR, CIHR and OGS funding. We are thankful for STTARR Imaging (UHN) for their help in this work, and for the contributions from all members of McMaster’s Radiochemistry Group and Dr. Sheila Singh’s research team at McMaster University.
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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".