Cationization of immunoglobulin G results in enhanced organ uptake of the protein after intravenous administration in rats and primate.
Cationization of proteins in general enhances the cellular uptake of these macromolecules, and cationized antibodies are known to retain antigen binding properties. Therefore, cationized antibodies may be therapeutic and allow for "intracellular immunization." The present studies test the hypothesis that the tissue uptake of cationized immunoglobulin G (IgG) after intravenous administration may be greatly increased relative to the uptake of native proteins. The pharmacokinetics of cationized immunoglobulin G clearance from blood, and the volume of distribution of the cationized or native protein (albumin, IgG) for 10 organs was measured both in anesthetized rats and in an anesthetized adult Macaca irus cynomologous monkey. Initial studies on brain showed that serum factors inhibited uptake of 125I-cationized IgG, but not 3H-cationized IgG. The blood-brain barrier permeability surface area product for 3H-cationized IgG was 0.57 +/- 0.04 microliters min-1 g-1. The ratio of the volume of distribution of the 3-H-cationized IgG compared to 3H-labeled native albumin ranged from 0.9 (testis) to 15.7 (spleen) in the rat at 3 hr after injection, and a similarly enhanced organ uptake was observed in the primate. In conclusion, these studies demonstrate that cationization of immunoglobulin greatly increases organ uptake of the plasma protein compared to native immunoglobulins, and suggest that cationization of monoclonal antibodies may represent a potential new strategy for enhancing the intracellular delivery of these proteins.
Triguero
D
D
Department of Medicine, University of California, Los Angeles School of Medicine.
Buciak
J L
JL
Pardridge
W M
WM
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D007074:Immunoglobulin G / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D008251:Macaca; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium
D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D012709:Serum Albumin; D014316:Tritium