Document Detail


Trifunctional antibody ertumaxomab: Non-immunological effects on Her2 receptor activity and downstream signaling.
MedLine Citation:
PMID:  22820509     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The trifunctional antibody ertumaxomab bivalently targets the human epidermal growth factor receptor 2 (Her2) on epithelial (tumor) cells and the T cell specific CD3 antigen, and its Fc region is selectively recognized by Fcγ type I/III receptor-positive immune cells. As a trifunctional immunoglobulin, ertumaxomab therefore not only targets Her2 on cancer cells, but also triggers immunological effector mechanisms mediated by T and accessory cells (e.g., macrophages, dendritic cells, natural killer cells). Whether molecular effects, however, might contribute to the cellular antitumor efficiency of ertumaxomab are largely unknown.
METHODS: Potential molecular effects of ertumaxomab on Her2-overexpressing BT474 and SK-BR-3 breast cancer cells were evaluated. The dissociation constant Kd of ertumaxomab was calculated from titration curves that were recorded by flow cytometry. Treatment-induced changes in Her2 homodimerization were determined by flow cytometric fluorescence resonance energy transfer measurements on a cell-by-cell basis. Potential activation / deactivation of Her2, ERK1/2, AKT and STAT3 were analyzed by western blotting, Immunochemistry and immunofluorescent cell staining.
RESULTS: The Kd of ertumaxomab for Her2-binding was determined at 265 nM and the ertumaxomab binding epitope was found to not overlap with that of the therapeutic anti-Her2 monoclonal antibodies trastuzumab and pertuzumab. Ertumaxomab caused an increase in Her2 phosphorylation at higher antibody concentrations, but changed neither the rate of Her2-homodimerization /-phosphorylation nor the activation state of key downstream signaling proteins analyzed.
CONCLUSIONS: The unique mode of action of ertumaxomab, which relies more on activation of immune-mediated mechanisms against tumor cells compared with currently available therapeutic antibodies for breast cancer treatment, suggests that modular or sequential treatment with the trifunctional bivalent antibody might complement the therapeutic activity of other anti-Her2/anti-ErbB receptor reagents.
Authors:
Simone Diermeier-Daucher; Olaf Ortmann; Stefan Buchholz; Gero Brockhoff
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-23
Journal Detail:
Title:  mAbs     Volume:  4     ISSN:  1942-0870     ISO Abbreviation:  MAbs     Publication Date:    2012 Sep-Oct
Date Detail:
Created Date:  2012-09-07     Completed Date:  2013-01-17     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  101479829     Medline TA:  MAbs     Country:  United States    
Other Details:
Languages:  eng     Pagination:  614-22     Citation Subset:  IM    
Affiliation:
Department of Gynecology and Obstetrics, University of Regensburg, Regensburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Bispecific / immunology*,  metabolism,  pharmacology*
Antibodies, Monoclonal / immunology*,  metabolism,  pharmacology*
Breast Neoplasms / metabolism,  therapy
Cell Line, Tumor
Epithelial Cells / metabolism*
Female
Humans
Receptor, erbB-2 / drug effects*,  metabolism
Signal Transduction*
Chemical
Reg. No./Substance:
0/Antibodies, Bispecific; 0/Antibodies, Monoclonal; 0/ertumaxomab; EC 2.7.10.1/Receptor, erbB-2
Comments/Corrections

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