Abstract P6-11-05: ANG4043, a brain-penetrant anti-HER2 mAb increases survival in mice bearing intracranial BT-474 breast tumor cells
Bibliographic record
Abstract
Abstract Background: Treatment options for metastatic brain tumors originating from HER2-positive breast disease are limited due to the inability of most anti-tumor agents to enter the brain. While the selectively permeable blood-brain barrier (BBB) restricts access of therapeutics such as mAbs to the brain, transcytosis of hormones, nutrients, and other homeostatic modulators is mediated by transporters and endogenous receptors such as the low density lipoprotein receptor-related protein 1 (LRP1). We have created a family of peptides (Angiopeps) that are recognized by LRP1 and enter the brain via receptor-mediated transcytosis. Using these proprietary Angiopeps, we have created novel, brain-penetrant Peptide-Drug Conjugates. An iterative process of linker selection and reaction condition optimization led to the discovery of ANG4043, a conjugate of the peptide Angiopep-2 (An2) and an anti-HER2 mAb similar to trastuzimab. This brain-penetrant An2-mAb conjugate, which displays HER2 binding affinity and in vitro anti-proliferative properties similar to that of the native mAb, was tested in a murine model of breast tumor brain metastases. Methods: Athymic nude mice were stereotactically implanted 1.5 mm anterior and 2.5 mm lateral to bregma with 1×106 BT-474 cells twelve days prior to initiation of drug treatment. Body weight and morbidity/mortality were monitored daily. Separate groups of mice received mAbs that were labeled with the fluorescent probe Cyto-750 to allow for near infrared in vivo imaging. Results: Median survival in the control group was 45 days, compared with 68 days and 80 days for the 5 mg/kg (p = 0.0005) and 15 mg/kg (p = 0.0003) groups, respectively, demonstrating a 51% and 78% improvement over the control group. In addition, a greater degree of fluorescence was observed in intracranial BT-474 brain tumors in the ANG4043 group compared to the native anti-HER2 mAb group. Conclusions: These data demonstrate that ANG4043 reaches its target in brain tumors and increases survival in a mouse HER2-positive intracranial tumor model. These results extend the validation of An2 conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs for development of new brain-penetrant anti-tumor therapeutics. We intend to progress this program to clinical stages both as monotherapy and in combination with ANG1005, the An2-paclitaxel conjugate that has shown encouraging results in clinical studies with primary brain tumors and breast cancer brain metastases. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-05.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".