Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action

Area of Science:

• Oncology
• Molecular Biology
• Immunotherapy

Background:

• HER2 (Human Epidermal growth factor Receptor 2) is a key oncogenic driver in various cancers, often amplified, leading to overexpression, increased signaling, and uncontrolled cell proliferation.
• Tumor cells frequently exhibit addiction to oncogenes like HER2, presenting a therapeutic vulnerability for targeted interventions.

Purpose of the Study:

• To design and evaluate a novel anti-HER2 biparatopic and tetravalent IgG fusion molecule with a multimodal mechanism of action.
• To investigate the molecule's ability to induce HER2 clustering, internalization, and degradation, and compare its efficacy against existing HER2-targeted therapies.

Main Methods:

• Design of a biparatopic and tetravalent IgG fusion targeting specific epitopes on HER2 in a defined geometric arrangement.
• Assessment of HER2 clustering, surface receptor mobility, internalization, and degradation.
• In vitro evaluation of the fusion molecule's inhibitory effect compared to trastuzumab, pertuzumab, and parental monoclonal antibodies (mAbs).
• In vivo efficacy testing in a HER2-amplified cancer xenograft model.

Main Results:

• The designed tetravalent IgG fusion induced HER2 clustering, leading to reduced surface HER2 mobility.
• Unlike previous binders, this construct robustly internalized and quantitatively degraded clustered HER2.
• The multimodal mechanism was dependent on specific epitope targeting and geometric arrangement within the tetravalent construct.
• The single-agent efficacy of the novel antibody surpassed the combination of trastuzumab and pertuzumab in vitro and demonstrated effectiveness in a xenograft model.

Conclusions:

• A novel anti-HER2 biparatopic tetravalent IgG fusion exhibits a unique multimodal mechanism of action involving HER2 clustering, internalization, and degradation.
• This engineered antibody demonstrates superior in vitro efficacy compared to current standard-of-care HER2-targeted therapies and shows promise in preclinical in vivo models.
• The findings highlight the potential of precisely engineered multivalent antibodies for overcoming resistance and improving therapeutic outcomes in HER2-driven cancers.