Development and preclinical evaluation of an asialoglycoprotein receptor 1-targeted antibody-drug conjugate in hepatic inflammation.

Authors

Vineesh Indira Chandran, Stig Hill Christiansen, Sandra Maria Hansen, Anne-Novera Larsen, Stine Marie Præstholm, Nicolaj Toft, Yaseelan Palarasah, Maria Kløjgaard Skytthe, Søren Kragh Moestrup, Lars Grøntved, Changzhu Wu, Thomas Lykke-Møller Sørensen, Henricus Antonius Maria Mutsaers, Jonas Heilskov Graversen

Published in

International journal of biological macromolecules. Pages 153145. Jun 21, 2026. Epub Jun 21, 2026.

Abstract

Hepatic inflammation leads to progressive conditions such as metabolic dysfunction-associated steatohepatitis, cirrhosis, liver cancer, or failure. Due to the high prevalence rates of hepatitis-induced serious liver pathologies, effective interventions are needed. In this study, we developed an antibody-drug conjugate (ADC) from an in-house generated and well characterized monoclonal antibody targeting asialoglycoprotein receptor 1 (ASGPR1) in hepatocytes. The mAb showed strong affinity for ASGPR1 protein with a K_D value of 4.2 ± 0.55 nM and high specificity for ASGPR1 in primary hepatocytes and mice liver tissues. After confirming the biodistribution of mAb ASGPR1 in the liver, we employed AAV8-TBG vector enabled green fluorescent protein (GFP)-labeled hepatocytes to validate the specific localization of mAb ASGPR1 to liver hepatocytes. Immunofluorescence analysis showed >80% hepatocytes expressing the GFP reporter and low uptake in other cells. Further, to establish mAb ASGPR1-mediated drug delivery, an anti-inflammatory drug dexamethasone (DEX) was conjugated to mAb ASGPR1 through an ester linker generating mAb ASGPR1-DEX ADC. mAb ASGPR1-DEX conjugate was stable and did not undergo nonspecific cleavage in plasma over 6 days at 37 °C. Besides, mAb ASGPR1-DEX ADC retained binding specificity and affinity toward ASGPR1 comparable to those of the unconjugated mAb ASGPR1 antibody. The mAb ASGPR1-DEX conjugate exhibited significant efficacy against lipopolysaccharide-induced hepatic inflammation by attenuating levels of interleukin-6, interleukin-1beta, and tumor necrosis factor in mouse precision cut liver slices and hepatocyte organoids. Collectively, these findings hold significant implications for mAb ASGPR1-based ADC as a promising therapeutic modality that warrants further investigation in inflammation-induced liver pathologies.

PMID:
42324007
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

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