Tailored Linker Chemistries for the Efficient and Selective Activation of ADCs with KSPi Payloads

Area of Science:

• Biochemistry
• Oncology
• Drug Delivery

Background:

• Antibody-drug conjugates (ADCs) face challenges with therapeutic windows due to off-target toxicity from payload release or ADC uptake in healthy tissues.
• Unspecific payload release and healthy organ accumulation limit the clinical efficacy and safety of current ADCs.

Purpose of the Study:

• To engineer novel antibody-drug conjugates (ADCs) with linkers selectively cleaved by tumor-associated proteases.
• To enhance the safety and efficacy of ADCs by ensuring preferential payload activation within tumors.

Main Methods:

• Development of novel linker technologies for ADCs.
• Utilizing the tumor-associated protease legumain for selective linker cleavage.
• Engineering ADCs with linkers demonstrating broad peptide tolerance, including single asparagine residues.

Main Results:

• Successfully engineered ADCs with linkers efficiently and selectively cleaved by legumain.
• Demonstrated high potency and preferential activation of ADCs in tumor tissues compared to healthy tissues.
• Showcased broad applicability for tailored ADC design through legumain's tolerance for diverse linker peptides.

Conclusions:

• Novel legumain-cleavable linkers offer an advanced strategy for developing safer and more potent ADCs.
• This approach provides an additional layer of safety by ensuring tumor-specific payload release.
• The versatility of legumain-based linkers facilitates the tailored design of ADCs for improved therapeutic outcomes.