Abstract A247: BT2111, a new anticancer agent composed of trastuzumab and transcend a vector for brain delivery for the treatment of metastatic Her2+ breast cancer.
Bibliographic record
Abstract
Abstract Background: The blood-brain barrier (BBB) is mainly formed by brain capillary endothelial cells, which are closely sealed by tight junctions and express high levels of active efflux transport proteins, including P-glycoprotein (Pgp). As a result, the overwhelming majority of small molecules, proteins such as antibodies do not cross the BBB. For example, a humanized monoclonal antibody, trastuzumab improves survival of patients with metastatic breast cancer that overexpress HER2. However, the breast cancer frequently progresses in the CNS probably a result from poor brain penetration of trastuzumab. BT2111 made by incorporating Transcend (Melanotransferrin, MTf, p97) a brain delivery vector to trastuzumab was manufactured to provide a non-invasive and flexible platform for transporting an active agent into the brain. Material and Methods: Brain distribution of Transcend, trastuzumab, and BT2111 was done by fluorescence confocal microscopy of brain slices after i.v. injection of rhodamine labeled molecules. Therapeutical efficacy was assessed in a mice model characterized by the formation of brain metastases after intracardiac administration of MDA-MB 231BR. A biweekly treatment was initiated on day 21 after the initial intracardiac injections. The efficacy of the different compounds was assessed by counting the number and size of metastases in brain at the termination of the experiment. Results: We demonstrate that an antibody, trastuzumab, labelled with rhodamine can be transported in the brain parenchyma after incorporation of MTf. By quantitative confocal fluorescence microscopy we determined that 10 to 15 times more antibodies were delivered in the brain parenchyma when conjugated to MTf. It was found that BT2111 reduces by 68% the number of human HER2+ breast cancer metastases in the brain when compared to control animals with the remaining tumors being 57% smaller than those in the control animals. In contrast, trastuzumab alone had no effect on reducing the number of metastases and was associated with only a slight reduction in metastasis size when compared to untreated control animals. Conclusion: Transcend (MTf, p97) a brain delivery vector can be used to transport large biologics such as mAbs, trastuzumab, at therapeutic concentration to the brain parenchyma for the treatment of brain cancers. BT2111 has the potential to become a new anticancer agent, BT2111, for treatment of brain metastases. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A247. Citation Format: Reinhard Gabathuler, Timothy Z. Vitalis, Mohamed I. Nounou, Umar Iqbal, Maria Moreno, Chris E. Adkins, Tori O. Torrell, Wilfred A. Jefferies, Paul R. Lockman. BT2111, a new anticancer agent composed of trastuzumab and transcend a vector for brain delivery for the treatment of metastatic Her2+ breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A247.
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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) | 0.000 | 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) | 0.000 | 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".