Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Chemotherapy resistance in progressive cancers poses a significant clinical challenge.
• Human epidermal growth factor receptor 3 (HER3) is implicated in drug resistance to HER1- and HER2-targeted therapies.
• Existing anti-HER3 monoclonal antibodies (mAbs) like patritumab have shown limited clinical efficacy.

Purpose of the Study:

• To generate and characterize novel anti-HER3 mAbs with potentially improved therapeutic effects.
• To investigate the efficacy of these novel mAbs in preclinical cancer models.

Main Methods:

• Generation of rat monoclonal antibodies against HER3.
• Validation of antibody specificity using cell-based assays, siRNA knockdown, and CRISPR/Cas9 genome editing.
• Characterization of antibody binding, internalization, and inhibition of HER3 signaling pathways (NRG1 binding, phosphorylation).
• Assessment of anti-tumor activity in vitro and in vivo using human cancer cell lines and xenograft models.

Main Results:

• Seven novel rat anti-HER3 mAbs were generated, showing specific binding to HER3-expressing cells.
• One mAb inhibited patritumab binding, indicating a distinct epitope.
• The novel mAbs demonstrated strong internalization of cell-surface HER3, inhibited NRG1 binding and downstream signaling, and suppressed cancer cell growth.
• One mAb (Ab4) significantly inhibited in vivo tumor growth of human colon cancer cells in nude mice.

Conclusions:

• Novel anti-HER3 mAbs were successfully developed with specific binding and potent anti-tumor activity.
• These mAbs show potential for overcoming drug resistance and represent promising candidates for cancer therapy.
• The developed mAbs may offer advantages over existing anti-HER3 therapies and complement current anti-cancer treatments.