A Novel Hepatic-Targeting System for Therapeutic Cytokines That Delivers to the Hepatic Asialoglycoprotein Receptor, but Avoids Receptor-Mediated Endocytosis
Tóm tắt
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 (GalNAc)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)3—IL-2 were more rapid than (Gal)3—IL-2. The ratio of the rate constant representing dissociation from the cell-surface receptor (koff) to that representing endocytosis of the ligand (kint) was greater for (Gal)3—IL-2 than (GalNAc)3—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—IL-2 was present in the hepatic extracellular space for a longer period than (GalNAc)3 IL-2.
Conclusions. The (Gal)3 ligand increases the therapeutic efficacy of IL-2 by enhancing its exposure to the cell-surface. The koff/kint affects the targeting efficacy of the conjugates to ASGP-R.
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