title: Differential inhibitory effect of L-lysine on renal accumulation of 67Cu-labelled F(ab')2 fragments in mice.
abstract: The basic amino acid L-lysine was administered to mice in an attempt to circumvent unwanted renal accumulation of 67Cu-labelled F(ab')2 fragments derived from the anti-NCAM IgG1, SEN7 and anti-CEA IgG1 monoclonal antibody (MAb)35. In control experiments, significant renal uptake of both 67Cu-labelled F(ab')2 fragments was observed, radiolabel being primarily localised to proximal tubules in the renal cortex. Following optimised L-lysine dosing protocols, renal uptake of 67Cu-MAb35 F(ab')2 was inhibited by up to 42%. Surprisingly, little inhibition (< 10%) of 67Cu-SEN7 F(ab')2 uptake was observed. Experiments to investigate this differential inhibition indicated that inhibition of MAb35 F(ab')2 uptake was relatively short-lived (approx. 6 hr), whilst no apparent differences were found in blood clearance rates between either 67Cu-F(ab')2 fragment. L-lysine administration caused a significant diuresis with high levels of intact 67Cu-labelled SEN7 and MAb35 F(ab')2 appearing in the urine, possibly due to blockade of renal uptake and lysine-induced increases in glomerular membrane permeability. Iso-electric focusing studies failed to identify any charge differences between the 67Cu-labelled F(ab')2 fragments, although a cathodal migration of all 67Cu-labelled samples, presumably due to the net positive charge conferred by addition of 67Cu2+ ions, was observed. Our results demonstrate that in addition to net charge, other unidentified characteristics may influence renal accumulation of radiometal-labelled F(ab')2 fragments and their inhibition by L-lysine.
authors.affiliation: Division of Radiopharmacy, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: R A
authors.initials: RA
authors.lastname: Rutherford
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.forename: R
authors.initials: R
authors.lastname: Waibel
authors.forename: P A
authors.initials: PA
authors.lastname: Schubiger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003301:Copper Radioisotopes; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000302:isolation & purification / Q000378:metabolism* / Q000652:urine; D007074:Immunoglobulin G / Q000378:metabolism; D007526:Isoelectric Point; D007553:Isotope Labeling; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D008239:Lysine / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D019006:Neural Cell Adhesion Molecules / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D003301:Copper Radioisotopes; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D019006:Neural Cell Adhesion Molecules; D008239:Lysine