Site-specific antibody-polymer conjugates for siRNA delivery

Area of Science:

• Bioconjugation Chemistry
• Molecular Therapeutics
• Cancer Biology

Background:

• Targeted delivery of nucleic acid therapeutics remains a challenge.
• Antibody-polymer conjugates (APCs) offer potential for site-specific drug delivery.
• HER2-positive cancers represent a significant therapeutic target.

Purpose of the Study:

• To develop and characterize site-specific antibody-polymer conjugates (APCs) for targeted siRNA delivery.
• To evaluate the impact of conjugation site on APC efficacy and gene silencing.
• To assess the potential of APCs as a platform for nucleic acid-based therapies.

Main Methods:

• Synthesis of antibody-polymer conjugates using genetically encoded p-acetyl phenylalanine.
• Characterization of APC binding affinity and cellular cytotoxicity.
• In vitro evaluation of siRNA delivery and gene silencing in HER2-positive cells.

Main Results:

• APCs demonstrated comparable binding affinity to native antibodies with no significant cytotoxicity.
• Specific APC variants successfully delivered siRNAs to HER2-positive cells, mediating potent mRNA and protein level gene silencing.
• One APC variant, despite high binding affinity, failed to induce gene silencing, highlighting the importance of conjugation site.

Conclusions:

• Chemically defined APCs are a viable platform for targeted siRNA delivery.
• The site of conjugation on the antibody significantly influences the therapeutic activity of APCs.
• These findings underscore the importance of rational design in developing antibody-polymer-based therapeutics.