Abstract 2465: Targeting HER2-positive brain metastases by incorporating the brain-penetrant Angiopep-2 peptide to an anti-HER2 antibody and anti-HER2 antibody drug conjugate
Bibliographic record
Abstract
Abstract Monoclonal antibodies directed against receptor tyrosine kinases such as HER2 have been demonstrated to reduce tumor size and increase survival. However, these agents achieve little to no brain penetration, making them ineffective against metastatic brain tumors. The blood-brain barrier (BBB), efficient at restricting entry of proteins such as mAbs and anticancer drugs into the brain, is comprised of capillary endothelial cells with tight junctions and efflux pumps. We have created a family of peptides (Angiopeps) which use receptor-mediated transcytosis to enter the brain. Conjugation of the Angiopep-2 (An2) to confer brain permeability has been validated for small molecules (ANG 1005, Phase II), peptides and proteins. The brain-penetrant An2 has also been incorporated to a humanized anti-HER2 mAb. This Angiopep-Antibody Conjugate, ANG4043, displays HER2 binding affinity and in vitro cytotoxic potency similar to that of native anti-HER2. ANG4043 demonstrates a high rate of entry into the brain. ANG4043 reduces the tumor size of BT-474 human breast cancer cells when implanted in the brain, consistent with achieving therapeutic concentrations. Here we describe chemical conjugation between three molecules: the An2, a cytotoxic drug (docetaxel or maytansine), and a mAb directed against HER2. These new An2-antibody-drug-conjugates (An2-ADCs) show a higher in vitro anti-proliferative potency than unconjugated mAb against HER2+ BT-474 and HC-19554 cells that are sensitive and resistant to Herceptin, respectively. Furthermore, they demonstrate a high rate of entry into the brain when compared to controls, leading to a reduction in brain tumor size and to an increase in the survival of mice bearing intracranial BT-474 tumors. Furthermore, An2-anti-HER2 derivatives are also efficacious in peripheral tissues since they inhibited the growth of subcutaneous BT-474 luciferase tumors. Overall, these data demonstrate that the conjugation of an Angiopep to therapeutic mAbs or ADCs can increase their efficacy in the CNS without affecting their anticancer properties outside of the brain. These results extend the validation of Angiopep conjugation beyond small anticancer drugs to include larger molecules such as therapeutic mAbs and ADCs for development of new brain-penetrant therapeutics for brain malignancies. Citation Format: Michel Demeule, Sanjoy Das, Christian Che, Gaoqiang Yang, Jean-Christophe Currie, Simon Lord-Dufour, Sasmita Tripathy, Anthony Regina, Jean-Paul Castaigne, Jean E. Lachowicz. Targeting HER2-positive brain metastases by incorporating the brain-penetrant Angiopep-2 peptide to an anti-HER2 antibody and anti-HER2 antibody drug conjugate. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2465. doi:10.1158/1538-7445.AM2015-2465
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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) | 0.000 | 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) | 0.001 | 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 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".