<sup>225</sup> Ac/ <sup>89</sup> Zr-Labeled N4MU01 Radioimmunoconjugates as Theranostics Against Nectin-4–Positive Triple-Negative Breast Cancer
Bibliographic record
Abstract
Nectin-4 is an overexpressed biomarker in 60%–70% of triple-negative breast cancer (TNBC) cases and an ideal target for radiotherapy and PET imaging. In this study, theranostic radioimmunoconjugates were developed using a fully human anti–nectin-4 antibody (N4MU01). The imaging properties and therapeutic effectiveness of the radioimmunoconjugates were evaluated using TNBC models. <b>Methods:</b> N4MU01 was radiolabeled with <sup>89</sup>Zr and <sup>225</sup>Ac for imaging and radiotherapy, respectively, using TNBC xenograft and syngeneic models. Biodistribution and PET imaging of the [<sup>89</sup>Zr]Zr-deferoxamine (DFO)-N4MU01 radioimmunoconjugate was studied in mice bearing nectin-4–positive xenografts. Dosimetry and toxicity of [<sup>225</sup>Ac]Ac-Macropa-N4MU01 were studied in naïve BALB/c mice, and the therapeutic efficacy was evaluated with two doses of 13 or two doses of 18.6 kBq, administered 10 d apart in athymic BALB/c nude mice bearing either a human TNBC MDA-MB-468 xenograft or a human nectin-4–transfected 4T1 (4T1.<sub>nectin-4</sub>) syngeneic allograft. <b>Results:</b> The pharmacokinetic profile of the [<sup>89</sup>Zr]Zr-DFO-N4MU01 radioimmunoconjugate showed biphasic distribution with a moderate elimination half-life of 63 h. PET imaging and biodistribution of [<sup>89</sup>Zr]Zr-DFO-N4MU01 in mice bearing the MDA-MB-468 xenograft showed high tumor uptake of 13.2 ± 1.12 percent injected activity per gram at 120 h. [<sup>225</sup>Ac]Ac-Macropa-N4MU01 was effectively internalized in MDA-MB-468 and was cytotoxic to the cells with a 50% inhibition concentration of 1.2 kBq/mL. Toxicity studies revealed that 15 kBq of [<sup>225</sup>Ac]Ac-Macropa-N4MU01 was generally well tolerated, as indicated by hematologic, blood chemistry, and histopathologic analysis. Mice bearing MDA-MB-468 and 4T1.<sub>nectin-4</sub> xenografts treated with 13 kBq of [<sup>225</sup>Ac]Ac-Macropa-N4MU01 had 100% (6/6) and 83.3% (5/6) complete tumor remissions, respectively. <b>Conclusion:</b> The specific tumor uptake and remarkable effectiveness against aggressive TNBC tumors are very promising and warrant the clinical development of N4MU01 radioimmunoconjugates.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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 teacher head, 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".