On-demand cleavable linkers for radioimmunotherapy

Area of Science:

• Biochemistry
• Radiochemistry
• Oncology

Background:

• Radioimmunotherapy (RIT) shows promise for cancer treatment but faces challenges due to radiation exposure in healthy organs.
• Strategies are needed to protect vital organs while maintaining therapeutic doses to tumors.

Purpose of the Study:

• To develop a novel RIT strategy using cleavable linkers to rapidly remove radiometals from circulation after tumor accumulation.
• To identify and characterize specific linkers cleaved by an administered protease, enabling rapid renal clearance of radiometals.

Main Methods:

• Utilized a "one-bead-one-compound" (OBOC) combinatorial peptide library with fluorescent resonance energy transfer (FRET) for screening.
• Identified TNKase-specific on-demand cleavable (ODC) linkers resistant to plasma and tumor proteases.
• Employed D-amino acids flanking L-amino acids in peptide sequences for protease resistance.

Main Results:

• Successfully identified specific ODC linkers susceptible to TNKase cleavage.
• Demonstrated resistance of these linkers to common plasma and tumor-associated proteases.
• Established a method for on-demand radiometal release and clearance.

Conclusions:

• The developed ODC linker strategy offers a promising approach to mitigate off-target radiation toxicity in RIT.
• This method allows for controlled radiometal clearance, enhancing the therapeutic index of RIT.
• Further research can optimize linker design and protease selection for clinical translation.