Antibody mimetic drug conjugate manufactured by high-yield Escherichia coli expression and non-covalent binding...

Area of Science:

• Biotechnology
• Oncology
• Drug Development

Background:

• Antibody-drug conjugates (ADCs) are vital for advanced cancer treatment but face manufacturing and conjugation challenges.
• Cancer cells' genetic mutations often lead to resistance against single-target therapies.
• A need exists for therapeutics that simultaneously target multiple molecules with multiple payloads.

Purpose of the Study:

• To develop antibody mimetic-drug conjugates (AMDCs) as an alternative to traditional ADCs.
• To create a versatile platform for rapid, stable, and high-yield cancer therapeutics.
• To demonstrate the efficacy of AMDCs against HER2-positive cancer cells and in vivo models.

Main Methods:

• Engineered miniprotein antibodies fused to a streptavidin variant, expressed in E. coli.
• Utilized non-covalent payload binding via high-affinity streptavidin-iminobiotin interactions.
• Developed an AMDC targeting human epidermal growth factor receptor 2 (HER2) with a photo-activatable payload.

Main Results:

• Successfully created functional tetrameric AMDCs through refolding.
• The HER2-targeting AMDC demonstrated potent killing of cultured cancer cells.
• In vivo studies showed efficacy of the HER2-AMDC in a mouse xenograft model (KPL-4).

Conclusions:

• The developed AMDC platform overcomes limitations associated with traditional ADCs.
• AMDCs provide a promising strategy for developing next-generation cancer therapeutics.
• This platform allows for rapid development of stable, high-yield therapeutics against multiple targets.