Tumor Microenvironment-Responsive Antibody Fragment-Cleavable PEGylated Drug Conjugates (AFCDC) for Improved Tumor...

Area of Science:

• Biotechnology
• Oncology
• Drug Delivery

Background:

• Antibody-drug conjugates (ADCs) face challenges in solid tumor efficacy due to poor tumor penetration caused by their large size and strong binding.
• Antibody fragment-drug conjugates (FDCs) offer better penetration but suffer from rapid clearance, limiting their therapeutic retention.

Purpose of the Study:

• To develop a programmable Antibody Fragment-Cleavable PEGylated Drug Conjugate (AFCDC) platform to enhance ADC efficacy in solid tumors.
• To overcome the trade-off between penetration and retention seen in ADCs and FDCs.

Main Methods:

• Engineered genetically encoded bifunctional noncanonical amino acids for site-specific dual conjugation.
• Utilized pTAF to attach cytotoxic payloads and MMP2-cleavable PEG chains for controlled drug release and extended half-life.
• Evaluated AFCDC performance in HER2-positive tumor models, assessing intratumoral penetration, pharmacokinetics, and anti-tumor activity.

Main Results:

• AFCDC demonstrated improved intratumoral penetration and pharmacokinetics compared to traditional approaches.
• The platform successfully combined extended systemic half-life via PEGylation with enhanced tissue penetration upon PEG removal by tumor proteases.
• AFCDC showed enhanced anti-tumor activity over T-DXd in NCI-N87 xenografts under the evaluated regimen.

Conclusions:

• AFCDC technology effectively resolves the penetration-retention trade-off associated with antibody fragments.
• This programmable platform is versatile, compatible with various formats and payloads, offering a promising strategy to improve ADC efficacy in solid tumors.
• AFCDC represents a significant advancement in cancer therapeutics for solid tumor treatment.