Affibody-based HER2 prodrug shows conditional cytotoxic effect on HER2-positive cancer cells

Area of Science:

• Biotechnology
• Molecular Biology
• Cancer Therapeutics

Background:

• Therapeutic affinity proteins offer targeted cancer therapy by binding disease-associated molecules, often overexpressed receptors on tumor cells.
• On-target, off-tumor toxicity is a significant challenge due to the presence of target molecules in healthy tissues.
• Enhanced tumor selectivity is crucial for minimizing side effects in targeted cancer therapies.

Purpose of the Study:

• To develop and validate an affibody-based prodrug concept for enhanced tumor selectivity.
• To exploit tumor-associated proteases for the selective activation of prodrugs at the tumor site.
• To assess the efficacy and safety of HER2-specific affibody prodrugs in preclinical models.

Main Methods:

• Design and production of HER2-specific affibody prodrug candidates with distinct protease substrates.
• Assessment of prodrug activation by tumor-associated proteases and subsequent HER2 binding.
• Conjugation of the lead prodrug candidate to the cytotoxic agent DM1 for in vitro cytotoxicity evaluation in HER2-positive cancer cells.

Main Results:

• Successful design and characterization of HER2-specific affibody prodrugs.
• Demonstrated selective activation of prodrugs by corresponding tumor-associated proteases.
• The DM1-conjugated prodrug exhibited potent, HER2-dependent cytotoxicity with significantly reduced toxicity when prodrug activation was absent.

Conclusions:

• Affibody-based prodrugs activated by tumor-associated proteases represent a feasible strategy to enhance tumor selectivity.
• This approach holds promise for minimizing off-tumor toxicity in targeted cancer therapy.
• Further development of protease-activated prodrugs could lead to safer and more effective cancer treatments.