A bispecific HER2-targeting FynomAb with superior antitumor activity and novel mode of action

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• HER2 (Human Epidermal growth factor Receptor 2) is overexpressed in 20-30% of invasive breast cancers, making it a key therapeutic target.
• Current HER2-targeting therapies like trastuzumab and pertuzumab offer clinical benefits but face challenges with resistance.
• There is a critical need for novel therapeutic agents to overcome anti-HER2 resistance.

Purpose of the Study:

• To develop and characterize a new class of bispecific antibodies, FynomAbs, targeting multiple epitopes on HER2.
• To evaluate the efficacy of a specific FynomAb, COVA208, in preclinical models of HER2-positive breast cancer.
• To assess COVA208's potential to circumvent resistance mechanisms and enhance HER2-directed therapies.

Main Methods:

• Creation of bispecific FynomAbs by fusing antibodies with Fyn SH3-derived binding proteins.
• Detailed characterization of COVA208, including in vitro assays for HER2 internalization and apoptosis induction.
• In vitro and in vivo assessment of COVA208's impact on downstream HER2 signaling pathways and tumor growth in xenograft models.

Main Results:

• COVA208 demonstrated potent induction of HER2 internalization and apoptosis in vitro.
• Significant inhibition of downstream HER2 signaling pathways, reducing HER2, HER3, and EGFR levels, was observed both in vitro and in vivo.
• COVA208 exhibited superior anti-tumor activity compared to trastuzumab and pertuzumab across four distinct xenograft models.

Conclusions:

• The bispecific FynomAb COVA208 shows significant potential to overcome resistance and improve clinical outcomes in HER2-directed breast cancer therapy.
• COVA208 represents a promising new therapeutic candidate for HER2-positive cancers.
• This study establishes a paradigm for designing novel antibody-based therapeutics targeting multiple epitopes on receptor tyrosine kinases.