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Characterization of Asialoglycoprotein Receptor (ASGPR) Directed Hepatocellular Delivery Using a Pfizer Developed Targeting Ligand PF‐06853291
Author(s) -
Roy Marc,
Finley James,
Coskran Timothy,
Shen Amy,
Xia Shuhua,
Thuma Benjamin,
Mascitti Vincent
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.938.7
Subject(s) - asialoglycoprotein receptor , ligand (biochemistry) , chemistry , receptor , pharmacology , endocytosis , in vivo , pharmacokinetics , hepatocyte , biochemistry , microbiology and biotechnology , in vitro , medicine , biology
Asialoglycoprotein receptor (ASGPR) is a transmembrane protein that plays a critical role in serum glycoprotein homeostasis by mediating the endocytosis and lysosomal degradation of glycoproteins with exposed terminal galactose or N‐acetylgalactosamine. This receptor is highly expressed on hepatocytes while extra‐hepatic expression is minimal making the receptor an ideal candidate for targeted delivery of therapeutics to the liver (D'Souza, 2015). PF‐06853291 is an ASGPR ligand, discovered at Pfizer, conjugated to a fluorophore (Alexa Fluor® 647) and PF‐06868566 is a trivalent version of the natural ASGPR ligand N‐acetylgalactosamine (GalNAc) conjugated to the same fluorophore. This trivalent GalNac ligand is presently the standard for ASGPR mediated hepatic delivery both in preclinical studies and clinical trials (Chan, 2015; Rajeev, 2015; Simon, 2015). Demonstrating a more desirable hepatocellular delivery profile of the Pfizer ligand over current ligands in use would bolster confidence in using our internal ligand for hepatic delivery of therapeutics, including macromolecules. To this end, we have evaluated the hepatic bio‐distribution and pharmacokinetics of PF‐06853291 and PF‐06868566 in vivo following administration of a single intravenous (IV) dose in male C57BL/6N mice. Data from this study confirms each compound achieves similar serum exposure at early time points, and is rapidly cleared by a combination of liver accumulation and renal clearance. Quantification of PF‐06853291 and PF‐06969566 liver exposure by multiple endpoints demonstrates that the Pfizer trivalent ASGPR ligand facilitates increased ASGPR‐directed hepatocellular uptake and prolonged retention compared to the trivalent GalNAc. These results confirm the superiority of the Pfizer ASGPR ligand in hepatocellular delivery.