Antitumor Effects and Normal-Tissue Toxicity of <sup>111</sup>In-Nuclear Localization Sequence-Trastuzumab in Athymic Mice Bearing <i>HER</i>-Positive Human Breast Cancer Xenografts
Bibliographic record
Abstract
UNLABELLED: (111)In-nuclear localization sequence-trastuzumab is a radioimmunotherapeutic agent consisting of trastuzumab modified with NLS peptides (CGYGPKKKRKVGG) and labeled with the Auger electron emitter (111)In. Our objectives were to evaluate the tumor growth-inhibitory properties and normal-tissue toxicity of (111)In-NLS-trastuzumab in mice after intraperitoneal administration. METHODS: The pharmacokinetics of (111)In-NLS-trastuzumab after intravenous (tail vein) or intraperitoneal injection in BALB/c mice were compared. Normal-tissue toxicity was determined in BALB/c mice at 2 wk after intraperitoneal injection of 3.7-18.5 MBq (4 mg/kg) of (111)In-NLS-trastuzumab by monitoring body weight, histopathologic examination of tissues, and hematology (white blood cell, platelet, red blood cell, and hemoglobin) or clinical biochemistry (alanine transaminase and creatinine) parameters. A no-observable-adverse-effect-level (NOAEL) dose was defined. Athymic mice bearing subcutaneous MDA-MB-361 or MDA-MB-231 human breast cancer xenografts (5.0 x 10(5) or 0.5 x 10(5) HER2/cell, respectively) were treated with a single NOAEL dose or 2 doses administered intraperitoneally and separated by 2 wk. Control groups were administered (111)In-trastuzumab, trastuzumab, nonspecific (111)In-NLS-human IgG (hIgG), or normal saline. RESULTS: The bioavailability of (111)In-NLS-trastuzumab after intraperitoneal injection was 0.7. The NOAEL dose was 9.25 MBq (4 mg/kg); doses greater than or equal to 18.5 MBq decreased white blood cell or platelet counts, and doses of 27.7 MBq decreased red blood cell counts. There was no increase in alanine transaminase or creatinine at any doses tested. There were no morphologic changes to the liver, kidneys, heart, or spleen or loss of body weight. A single dose of (111)In-NLS-trastuzumab (9.25 MBq)-compared with mice receiving (111)In-trastuzumab, trastuzumab, (111)In-NLS-hIgG, or normal saline-significantly slowed the rate of growth of MDA-MB-361 tumors over 60 d (0.014 d(-1) vs. 0.033 d(-1), 0.046 d(-1), 0.030 d(-1), and 0.061 d(-1), respectively; P < 0.05). (111)In-NLS-trastuzumab had no effect on the growth of MDA-MB-231 tumors. Two doses of (111)In-NLS-trastuzumab (9.25 MBq; 4 mg/kg) separated by 2 wk increased the survival of mice with MDA-MB-361 tumors, compared with mice treated with trastuzumab or normal saline (>140 d vs. 96 and 84 d, respectively; P < 0.001 or 0.027, respectively). CONCLUSION: (111)In-NLS-trastuzumab is a promising radioimmunotherapeutic agent that could be effective for treatment of HER2-overexpressing breast cancer in humans.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".