title: Reduction of renal uptake of monoclonal antibody fragments by amino acid infusion.
abstract: The renal uptake of radiolabeled antibody fragments and peptides presents a problem in radioimmunodetection and therapy, compromising lesion sensitivity, especially with intracellularly-retained isotopes. Previously, we showed that cationic amino acids and their derivatives are capable of significantly reducing kidney uptake in animals. We report our initial clinical results of successful renal uptake reduction in five patients who underwent cancer radioimmunodetection with 99mTc-anti-CEA Fab' fragments.
  
  
  METHODS
  The patients were infused with two liters of a commercially-available nutritive amino acid solution (containing approximately 2.25 g/liter lysine-glutamate and 2.50 g/liter arginine), whereas 75 control patients received the same volume of saline (quantification of organ and tumor kinetics from conjugate whole-body views by ROI technique).
  
  
  RESULTS
  The renal uptake in the amino acid group was significantly lower (p<0.05) than in the control group (11.1 +/- 2.0% injected dose versus 17.7 +/- 7.0% injected dose at 24 hr postinjection), whereas the uptake of all other organs remained unaffected. Gel filtration chromatography of the urine taken from amino-acid-treated patients showed that a significantly higher amount of excreted activity was bound to intact Fab' (53% of excreted activity) in contrast to only less than 10% in the control group.
  
  
  CONCLUSIONS
  The renal uptake of monoclonal antibody fragments in patients can be reduced significantly by amino acid infusion, even at considerably lower doses than those that were safe and effective in animals. As was found in animals, the mechanism seems to rely on an inhibition of the re-absorption of tubularly-filtered proteins by the proximal tubule cells. These results encourage further clinical trials to lower the renal uptake experienced in radioimmunodetection, as well as in therapeutic trials with antibody fragments and peptides.
authors.affiliation: Garden State Cancer Center, Center for Molecular Medicine and Immunology, Newark, New Jersey 07103-2763, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Behr
authors.forename: W S
authors.initials: WS
authors.lastname: Becker
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: M E
authors.initials: ME
authors.lastname: Juweid
authors.forename: R M
authors.initials: RM
authors.lastname: Dunn
authors.forename: H J
authors.initials: HJ
authors.lastname: Bair
authors.forename: F G
authors.initials: FG
authors.lastname: Wolf
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
mesh_terms: D000368:Aged; D000596:Amino Acids / Q000008:administration & dosage / Q000494:pharmacology*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007262:Infusions, Intravenous; D007668:Kidney / Q000000981:diagnostic imaging* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016719:Radioimmunodetection; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000000981:diagnostic imaging; D013667:Technetium / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000596:Amino Acids; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D012965:Sodium Chloride; D013667:Technetium