| 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
|
| リソース情報 |
| ヒト・動物細胞 |
CW-2(RCB0778)
MKN-7(RCB3687) |
