Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Targeting human epidermal growth factor receptor 3 (HER3) is a promising strategy for cancer therapy.
• Novel drug conjugates offer potential for targeted delivery of cytotoxic agents.

Purpose of the Study:

• To investigate the efficacy and targeting capabilities of ZHER3-ABD-mcDM1, a novel HER3-targeting drug conjugate.
• To evaluate the in vitro and in vivo performance of ZHER3-ABD-mcDM1 for cancer treatment.

Main Methods:

• Synthesis and characterization of ZHER3-ABD-mcDM1, a conjugate of a HER3-targeting affibody, albumin-binding domain, and DM1 cytotoxic agent.
• In vitro assessment of HER3 binding affinity, cellular uptake, and cytotoxicity in HER3-overexpressing cell lines (BxPC-3).
• In vivo evaluation of a radiolabeled version ([99mTc]Tc-ZHER3-ABD-mcDM1) for biodistribution and tumor targeting in mouse xenograft models (pancreatic and prostate carcinoma).

Main Results:

• ZHER3-ABD-mcDM1 exhibited high affinity for HER3 (K_D 6 nM) and potent cytotoxicity against BxPC-3 cells (IC₅₀ 7 nM).
• Radiolabeled ZHER3-ABD-mcDM1 demonstrated significant internalization (27% after 8 h) and selective targeting of BxPC-3 and DU145 xenografts.
• In vivo studies showed peak tumor uptake of 6.3 ± 0.4% IA/g at 6 h in BxPC-3 xenografts, with expected biodistribution patterns.

Conclusions:

• ZHER3-ABD-mcDM1 is a potent and selective HER3-targeting drug conjugate with promising pre-clinical efficacy.
• The drug conjugate's ability to target HER3-overexpressing tumors warrants further investigation for clinical development in cancer therapy.