論文 - 詳細
| RRC ID | 65780 |
|---|---|
| 著者 | Kast F, Schwill M, Stüber JC, Pfundstein S, Nagy-Davidescu G, Rodríguez JMM, Seehusen F, Richter CP, Honegger A, Hartmann KP, Weber TG, Kroener F, Ernst P, Piehler J, Plückthun A. |
| タイトル | Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action. |
| ジャーナル | Nat Commun |
| Abstract |
The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model. |
| 巻・号 | 12(1) |
| ページ | 3790 |
| 公開日 | 2021-6-18 |
| DOI | 10.1038/s41467-021-23948-6 |
| PII | 10.1038/s41467-021-23948-6 |
| PMID | 34145240 |
| PMC | PMC8213836 |
| MeSH | Animals Antibodies, Monoclonal / immunology Antibodies, Monoclonal / therapeutic use* Antibodies, Monoclonal, Humanized / therapeutic use Antineoplastic Agents, Immunological / therapeutic use* Breast Neoplasms / therapy* Cell Line, Tumor Cell Proliferation / drug effects Drug Design Female HeLa Cells Humans Immunoglobulin G / immunology Immunotherapy / methods MCF-7 Cells Mice Mice, SCID Receptor, ErbB-2 / antagonists & inhibitors* Receptor, ErbB-2 / immunology* Trastuzumab / therapeutic use Xenograft Model Antitumor Assays |
| IF | 12.121 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | CW-2(RCB0778) MKN-7(RCB3687) |