A Novel Fc-Engineered Anti-HER2 Bispecific Antibody With Enhanced Antitumor Activity

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Human epidermal growth factor receptor 2 (HER2) overexpression is prevalent in various cancers.
• Anti-HER2 monoclonal antibodies (mAbs) are effective but not universally beneficial.
• Fragment crystallizable (Fc) engineering enhances therapeutic mAb efficacy.

Purpose of the Study:

• To engineer the Fc region of an anti-HER2 bispecific mAb (BiHT) to improve its therapeutic potential.
• To evaluate the efficacy of the Fc-engineered BiHT (MBiHT) in preclinical models.

Main Methods:

• Constructed Fc-engineered BiHT (MBiHT) using variable domains of trastuzumab and hersintuzumab.
• Assessed MBiHT binding affinity to HER2 and its subdomains.
• Evaluated MBiHT's ability to inhibit cancer cell proliferation, downregulate HER2 expression, and suppress downstream signaling.
• Measured antibody-dependent cellular cytotoxicity (ADCC) and in vivo efficacy in ovarian xenograft models.

Main Results:

• MBiHT exhibited similar binding affinity to HER2 as BiHT.
• MBiHT effectively inhibited proliferation, downregulated HER2, and suppressed signaling pathways.
• MBiHT demonstrated enhanced ADCC activity against tumor cell lines compared to BiHT.
• MBiHT showed superior inhibition of ovarian xenograft tumor growth in vivo.

Conclusions:

• Fc engineering of BiHT resulted in MBiHT with improved therapeutic properties.
• MBiHT exhibits enhanced ADCC and potent antitumor activity.
• MBiHT represents a promising therapeutic candidate for HER2-overexpressing cancers.