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A Tetravalent Biparatopic Antibody Causes Strong HER2 Internalization and Inhibits Cellular Proliferation
Filippo Benedetti1, Katharina Stadlbauer1, Gerhard Stadlmayr1
1Christian Doppler Laboratory for Innovative Immunotherapeutics, Institute of Molecular Biotechnology, Department of Biotechnology, University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna, Austria.
Abstract:
The overexpression of tyrosine kinase HER2 in numerous cancers, connected with fierce signaling and uncontrolled proliferation, makes it a suitable target for immunotherapy. The acquisition of resistance to currently used compounds and the multiplicity of signaling pathways involved prompted research into the discovery of novel binders as well as treatment options with multiple targeting and multispecific agents. Here we constructed an anti-HER2 tetravalent and biparatopic symmetrical IgG-like molecule by combining the Fab of pertuzumab with a HER2-specific Fcab (Fc fragment with antigen binding), which recognizes an epitope overlapping with trastuzumab. In the strongly HER2-positive cell line SK-BR-3, the molecule induced a rapid and efficient reduction in surface HER2 levels. A potent anti-proliferative effect, specific for the HER2-positive cell line, was observed in vitro, following the induction of apoptosis, and this could not be achieved with treatment with the mixture of pertuzumab and the parental Fcab. The inhibitory cytotoxic effect of our antibody as a single agent makes it a promising contribution to the armory of anti-cancer molecules directed against HER2-addicted cells.
Insights
A novel tetravalent, biparatopic anti-HER2 antibody effectively reduces HER2 levels and inhibits cancer cell proliferation by inducing apoptosis. This engineered molecule shows superior efficacy compared to existing treatments for HER2-positive cancers.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- HER2 overexpression drives cancer progression and resistance to therapies.
- Novel therapeutic strategies are needed to overcome resistance and target multiple pathways.
Purpose of the Study:
- To construct and evaluate a novel tetravalent, biparatopic anti-HER2 IgG-like molecule.
- To assess its efficacy in reducing HER2 levels and inhibiting proliferation in HER2-positive cancer cells.
Main Methods:
- Engineered a tetravalent, biparatopic IgG-like molecule combining pertuzumab Fab with a HER2-specific Fcab.
- Tested the molecule's ability to reduce surface HER2 levels on SK-BR-3 cells.
- Evaluated in vitro anti-proliferative effects and apoptosis induction in HER2-positive cell lines.
Main Results:
- The engineered molecule rapidly and efficiently reduced surface HER2 levels on SK-BR-3 cells.
- Demonstrated potent, HER2-specific anti-proliferative effects in vitro.
- Induced apoptosis, outperforming a combination of pertuzumab and parental Fcab.
Conclusions:
- The novel tetravalent, biparatopic anti-HER2 antibody is a promising single-agent therapeutic.
- It offers a potential new strategy against HER2-addicted cancers, overcoming limitations of current treatments.
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