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  • Title: A novel hepatic-targeting system for therapeutic cytokines that delivers to the hepatic asialoglycoprotein receptor, but avoids receptor-mediated endocytosis.
    Author: Sato H, Kato Y, Hayasi E, Tabata T, Suzuki M, Takahara Y, Sugiyama Y.
    Journal: Pharm Res; 2002 Nov; 19(11):1736-44. PubMed ID: 12458681.
    Abstract:
    PURPOSE: To demonstrate the utilities of a synthetic low-affinity ligand ((Gal)3) for the asialoglycoprotein receptor (ASGP-R) as a hepatic targeting device for therapeutic cytokines. METHODS: The site-specific incorporation of (Gal)3 or a typical high-affinity ligand (GaINAc)3 into IL-2 was catalyzed by microbial transglutaminase. The anti-tumor activities, pharmacokinetic profiles and receptor-mediated endocytosis in hepatocytes of the ligand-IL-2 conjugates were examined in mouse. RESULTS: The (Gal)3 has approximately 50 times lower affinity to ASGP-R than (GalNAc)3. Nevertheless, the antitumor effects were in the order of (Gal)3-IL-2 > unmodified IL-2 > (GalNAc)3-IL-2. The systemic elimination and the hepatic uptake of (GalNAc)374L-2 were more rapid than (Gal)3-IL-2. The ratio of the rate constant representing dissociation from the cell-surface receptor (k(off) to that representing endocytosis of the ligand (k(int) was greater for (Gal)3-IL-2 than (GalNAc)s-IL-2, suggesting that (Gal)3-IL-2 preferably avoids internalization due to its lower affinity to the receptor. The simulation studies demonstrated that (Gal)3-L-2 was present in the hepatic extracellular space for a longer period than (GaINAc)3 IL-2. CONCLUSIONS: The (Gal)3 ligand increases the therapeutic efficacy of IL-2 by enhancing its exposure to the cell-surface. The k(off)/k(int) affects the targeting efficacy of the conjugates to ASGP-R.
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