Targeted Delivery of LXR Agonist Using a Site-Specific Antibody-Drug Conjugate

Area of Science:

• Immunology
• Pharmacology
• Bioconjugation

Background:

• Liver X receptor (LXR) agonists show therapeutic promise for atherosclerosis by enhancing reverse cholesterol transport and reducing inflammation.
• On-target hepatotoxicity due to excessive lipogenesis limits the clinical application of conventional LXR agonists.

Purpose of the Study:

• To develop a novel antibody-drug conjugate (ADC) for targeted delivery of LXR agonists to monocytes/macrophages, thereby avoiding liver toxicity.
• To evaluate the efficacy and specificity of the CD11a-targeted LXR agonist ADC in vitro.

Main Methods:

• Site-specific incorporation of unnatural amino acids into anti-CD11a IgG to create a chemically defined ADC.
• Conjugation of an aminooxy-modified LXR agonist to anti-CD11a IgG via a cathepsin B-cleavable oxime linkage.
• Assessment of LXR activation in human THP-1 monocyte/macrophage cells and hepatocytes.

Main Results:

• The anti-CD11a IgG-LXR agonist ADC demonstrated specific LXR activation in CD11a-expressing THP-1 cells (EC50 = 27 nM).
• No significant LXR activation was observed in hepatocytes, confirming CD11a-mediated, tissue-specific payload delivery.
• The ADC achieved a 3-fold higher LXR activation compared to the conventional synthetic agonist T0901317.

Conclusions:

• A novel, site-specific ADC strategy enables targeted delivery of LXR agonists to monocytes/macrophages.
• This approach effectively overcomes the hepatotoxicity associated with conventional LXR agonists.
• The developed ADC holds potential for treating atherosclerosis and other LXR-mediated diseases with improved safety and efficacy.