Biparatopic HER2-targeted nanobody binder synergizes with trastuzumab in resistant tumor cells

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• Human epidermal growth factor receptor 2 (HER2) is a critical oncogenic driver in various solid tumors.
• While HER2-targeted therapies like trastuzumab and pertuzumab offer clinical benefits, resistance remains a significant hurdle.
• Development of next-generation HER2-targeting agents is crucial for improved cancer treatment.

Purpose of the Study:

• To engineer and evaluate a novel biparatopic nanobody-based binder targeting distinct domains of HER2.
• To assess the efficacy of this new agent in HER2-expressing and trastuzumab-resistant cancer models.
• To elucidate the mechanism of action of the biparatopic binder.

Main Methods:

• Engineering of a biparatopic nanobody-based binder (A9F5-H2F5-Fc, AH) targeting extracellular domains I and II of HER2.
• Assessment of receptor saturation, internalization, and degradation in HER2-expressing tumor cells.
• Evaluation of synergistic antitumor efficacy in trastuzumab-resistant cancer cells in combination with trastuzumab.
• Structural modeling to predict the binding mode and HER2 clustering.

Main Results:

• The engineered binder AH demonstrated greater HER2 receptor saturation, internalization, and degradation compared to trastuzumab plus pertuzumab.
• AH exhibited superior synergistic antitumor efficacy in combination with trastuzumab in trastuzumab-resistant cancer cells.
• Structural modeling suggested a unique 'trans'-binding mode leading to multivalent HER2 clustering.

Conclusions:

• The rationally designed biparatopic nanobody binder AH shows potential to overcome trastuzumab resistance in HER2-positive cancers.
• Nanobody-based biparatopic strategies represent a promising approach for enhancing antitumor efficacy.
• AH offers a potential next-generation therapeutic strategy for HER2-driven malignancies.