Open AccessA combination of two antibodies recognizing non‐overlapping epitopes of HER 2 induces kinase activity‐dependent internalization of HER 2
Author(s) -
Szymanska Monika,
Fosdahl Anne M.,
Nikolaysen Filip,
Pedersen Mikkel W.,
Grandal Michael M.,
Stang Espen,
Bertelsen Vibeke
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12899
Subject(s) - internalization , endocytic cycle , epitope , endocytosis , antibody , monoclonal antibody , epidermal growth factor receptor , receptor , biology , phosphorylation , kinase , epidermal growth factor , microbiology and biotechnology , chemistry , biochemistry , immunology
The human epidermal growth factor receptor 2 ( HER 2/ErbB2) is overexpressed in a number of human cancers. HER 2 is the preferred heterodimerization partner for other epidermal growth factor receptor ( EGFR ) family members and is considered to be resistant to endocytic down‐regulation, properties which both contribute to the high oncogenic potential of HER 2. Antibodies targeting members of the EGFR family are powerful tools in cancer treatment and can function by blocking ligand binding, preventing receptor dimerization, inhibiting receptor activation and/or inducing receptor internalization and degradation. With respect to antibody‐induced endocytosis of HER 2, various results are reported, and the effect seems to depend on the HER 2 expression level and whether antibodies are given as individual antibodies or as mixtures of two or more. In this study, the effect of a mixture of two monoclonal antibodies against non‐overlapping epitopes of HER 2 was investigated with respect to localization and stability of HER 2. Individual antibodies had limited effect, but the combination of antibodies induced internalization and degradation of HER 2 by multiple endocytic pathways. In addition, HER 2 was phosphorylated and ubiquitinated upon incubation with the antibody combination, and the HER 2 kinase activity was found to be instrumental in antibody‐induced HER 2 down‐regulation.