Diermeier-Daucher, Simone and Ortmann, Olaf and Buchholz, Stefan and Brockhoff, Gero (2012) Trifunctional antibody ertumaxomab Non-immunological effects on Her2 receptor activity and downstream signaling. MABS, 4 (5). pp. 614-622. ISSN 1942-0862, 1942-0870
Full text not available from this repository. (Request a copy)Abstract
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 Fc gamma 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. Results: The K-d 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. Methods: Potential molecular effects of ertumaxomab on Her2-overexpressing BT474 and SK-BR-3 breast cancer cells were evaluated. The dissociation constant K-d 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. 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | METASTATIC BREAST-CANCER; BY-CELL BASIS; LASTING ANTITUMOR IMMUNITY; RESONANCE ENERGY-TRANSFER; BISPECIFIC ANTIBODY; TUMOR-CELLS; MONOCLONAL-ANTIBODIES; TRANSFER EFFICIENCY; TRASTUZUMAB; PERTUZUMAB; ertumaxomab; trifunctional antibody; anti-Her2 targeting |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Frauenheilkunde und Geburtshilfe (Schwerpunkt Frauenheilkunde) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 May 2020 08:53 |
| Last Modified: | 06 May 2020 08:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18205 |
Actions (login required)
 |
View Item |
