Novel strategy for a bispecific antibody: induction of dual target internalization and degradation

Authors
Lee, J. M.Lee, S. H.Wang, J-HOh, S. J.Kim, B.Jung, S.Shim, S-hLin, P. W.Lee, S. B.Cho, M-YKoh, Y. J.Kim, S. Y.Ahn, S.Lee, J.Kim, K-mCheong, K. H.Choi, J.Kim, K-A
Issue Date
2016-08
Publisher
NATURE PUBLISHING GROUP
Citation
ONCOGENE, v.35, no.34, pp.4437 - 4446
Abstract
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.
Keywords
GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; C-MET ANTIBODY; TYROSINE KINASE INHIBITORS; ACQUIRED-RESISTANCE; RNA INTERFERENCE; IN-VIVO; THERAPY; MECHANISM; CETUXIMAB; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; C-MET ANTIBODY; TYROSINE KINASE INHIBITORS; ACQUIRED-RESISTANCE; RNA INTERFERENCE; IN-VIVO; THERAPY; MECHANISM; CETUXIMAB
ISSN
0950-9232
URI
https://pubs.kist.re.kr/handle/201004/123860
DOI
10.1038/onc.2015.514
Appears in Collections:
KIST Article > 2016
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE