Engineered multifunctional transforming growth factor-β type II receptor ectodomain fusions for oncology applications

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Transforming growth factor-β (TGF-β) plays a dual role in cancer, acting as a tumor suppressor early on but promoting tumorigenesis, metastasis, and chemoresistance in later stages.
• The pleiotropic nature of TGF-β presents a significant challenge for developing effective targeted therapies.

Purpose of the Study:

• To design and develop a novel class of TGF-β-targeting biotherapeutics.
• To create fusion proteins combining the TGF-β type II receptor ectodomain (TβRII-ED) with antibody fragments for targeted cancer therapy.

Main Methods:

• Constructed and characterized TβRII-ED-Fc fusion proteins.
• Assessed the in vitro neutralizing potency of fusions against different TGF-β isoforms.
• Evaluated the in vivo efficacy of TβRII-ED-Fc in neutralizing tumor-promoting TGF-β activities.

Main Results:

• TβRII-ED-Fc fusions demonstrated efficient TGF-β ligand trapping with picomolar potency against TGF-β1 and TGF-β3 isoforms.
• The TβRII-ED-Fc module proved versatile when combined with targeting moieties.
• These targeted fusions effectively neutralized tumor-promoting TGF-β activities in vivo.

Conclusions:

• TβRII-ED-Fc fusion proteins represent a novel and potent class of TGF-β-targeting therapeutics.
• This versatile ligand-trapping module can be engineered into powerful anticancer biotherapeutics.
• Targeted delivery and retention at the tumor site enhance the therapeutic potential of these agents.