Abstract 2905: The activity of a new class of biologics: trastuzumab conjugates designed to treat brain metastases of HER2+ breast cancers
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 the disease due to brain metastases. In these patients trastuzumab is no longer effective because the blood brain barrier reduces distribution of trastuzumab to the brain tumor. In this study, we conjugate trastuzumab to melanotransferrin (MTf), a protein of the transferrin family, which has been shown to cross the blood brain barrier, and characterize its anti-tumor activity. We used thiol-malemide linkage to conjugate trastuzumab to MTf and generated a mixture of trastuzumab-MTf species of varying molar ratios. Size exclusion chromatography was used to enriched for the 1:1 heterodimer fraction and this fraction was designated as BT2111. The activity of BT2111 against human HER2+ breast cancer cell lines was tested with a cytotoxicity assay, an antibody dependent cellular cytotoxicity (ADCC) assay, and in a peripheral tumor xenograft model. At equimolar equivalents, BT2111 had greater anti-tumor activity than trastuzumab against HER2+ human breast cancer cell lines (SKBR3 and BT474). Furthermore, significant ADCC activity directed against BT474 cells was observed when cells were treated with BT2111 and incubated with human NK cells. Finally, both BT2111 and trastuzumab completely inhibited the growth of peripheral xenograft tumors (BT474) in athymic mice over the course of the experimental period (5-6 weeks). Conjugation of trastuzumab to MTf does not alter the in vivo anti-tumor activity of trastuzumab, supporting the conclusion that HER2 binding and Fc receptor binding was not significantly affected by conjugation. BT2111 is the first example of a new class of biologics that demonstrates the ability to inhibit the growth of peripheral HER2+ tumors and has the added benefit of penetrating the brain for the treatment of HER2+ brain metastases. Citation Format: Timothy Vitalis, Wilfred Jefferies, Reinhard Gabathuler. The activity of a new class of biologics: trastuzumab conjugates designed to treat brain metastases of HER2+ breast cancers. [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 2905. doi:10.1158/1538-7445.AM2014-2905
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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".