Novel strategy for a bispecific antibody: induction of dual target internalization and degradation
| Autor: | Seung-Hyun Lee, Jesuk Lee, Seungbae Lee, Powei Lin, Byung-Uk Kim, Seung Ja Oh, Soomin Ahn, Jung-Dal Choi, Young Jun Koh, Shim Sh, Hwang Jw, Jong Kyun Lee, Kinam Kim, Sun Young Kim, Cho My, Kyoung-Mee Kim, Kwang-Ho Cheong, Sun-Tae Jung |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class Receptor ErbB-2 media_common.quotation_subject Monoclonal antibody Molecular oncology Receptor tyrosine kinase 03 medical and health sciences Mice 0302 clinical medicine Growth factor receptor ErbB Neoplasms Antibodies Bispecific Genetics medicine Animals Humans Epidermal growth factor receptor Internalization Molecular Biology media_common Cell Proliferation biology Proto-Oncogene Proteins c-met ErbB Receptors 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology biology.protein Cancer research Female Signal transduction Signal Transduction |
| Zdroj: | Oncogene. 35(34) |
| ISSN: | 1476-5594 |
| Popis: | Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers. |
| Databáze: | OpenAIRE |
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