Abstract 642: Transcend, a protein vector for brain delivery, allows trastuzumab to reach the brain at effective concentration after incorporation to form BT2111
Bibliographic record
Abstract
Abstract Trastuzumab, a monoclonal antibody against HER2, is an effective therapy for the treatment of peripheral HER2+ breast cancer. However a significant number of patients eventually succumb to metastases of the brain because the endothelial tight junctions of the blood-brain barrier prevent distribution of trastuzumab to the metastatic tumors. Improving distribution of trastuzumab to HER2+ brain tumors represents a major hurdle in the treatment of metastatic HER2+ breast cancer. Previous studies have shown that doxorubicin conjugated to melanotransferrin (MTf) increased significantly the survival of mice bearing intracranial tumors, while doxorubicin alone was not effective. In this study we examine the potential of MTf-trastuzumab conjugates (BT2111) to penetrate the blood-brain barrier. BT2111 and trastuzumab were labeled with fluorescent markers, either Cy5.5 or rhodamine. The cellular uptakes of these labeled proteins were studied with fluorescence microscopy in cultures of primary human brain endothelial cells (HBEC) and in HER2+ (A172, SKBR3, and BT474), and HER2- (MDA-MB-468) breast cancer cell lines. The fluorescent conjugates were also injected IV into mice and the distribution of BT2111 and trastuzumab to endothelial cells and brain parenchyma was compared with laser scanning confocal microscopy. To aid in the co-localization of BT2111 and trastuzumab to the brain vasculature, mice were injected with tomato lectin-FITC or anti CD31 IgG-FITC prior to sacrifice. The results showed that primary human brain endothelial cells (HBEC) took up BT2111 suggesting that BT2111 can interact with the MTf receptor and transport BT2111 into the intracellular compartment. In contrast, no specific staining associated with trastuzumab was observed, either on the surface or in the interior of HBECs. Uptake of both BT2111 and trastuzumab was observed on the surface of A172, SKBR3, and BT474 cells but not on MDA-MB-468 cells confirming that BT2111 retains HER2 binding activity. When BT2111 and trastruzumab were injected into mice, laser scanning confocal microscopy showed increased distribution of BT2111 in the brain parenchyma when compared to trastuzumab. 10 to 15 times more trastuzumab was delivered in the brain parenchyma when conjugated to MTf. Using a mice model characterized by the formation of brain metastasis after intracardiac administration of MDA-MB 231BR we show that BT2111 is homogenously distributed in normal brain and can reach therapeutical concentration in the brain using 10% of the predicted therapeutic IV dose when trastuzumab was administered as BT2111. These results indicate that BT2111 has the potential to become a new anti-cancer agent for treatment of HER2+brain metastases. Citation Format: Reinhard Gabathuler, Timothy Z. Vitalis, Mohamed I. Nounou, Chris E. Adkins, Paul R. Lockman, Wilfred A. Jefferies. Transcend, a protein vector for brain delivery, allows trastuzumab to reach the brain at effective concentration after incorporation to form BT2111. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 642. doi:10.1158/1538-7445.AM2014-642
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".