Reducing renal accumulation of single-chain Fv against melanoma-associated proteoglycan by coadministration of L-lysine.
In view of the rising melanoma incidence and the absence of effective treatments for metastatic disease, there is an urgent need for new methods that allow the early detection of melanoma. To this end, in vivo detection by patient imaging with single-chain Fv (scFv) antibody fragments is an attractive diagnostic approach. However, high non-specific accumulation of scFvs in the kidney reduces image quality in this body area and prevents the use of scFvs for melanoma radioimmunotherapy. We have tested the effect of coadministration of L-lysine with (125)I-labelled scFvs against melanoma-associated proteoglycan on kidney accumulation in a nude mouse xenograft model. Coadministration of L-lysine had no significant effect on tumour accumulation of scFvs or blood clearance, but decreased kidney accumulation by factors of 2.25, 2.3, 6.3 and 5.8, respectively, at 1, 3, 6 and 18 h post-injection, and improved tumour to muscle contrast. The reduction in kidney accumulation was maximal at time points that can be extrapolated to patient studies. The time dependence of the effect suggests that further improvements could be achieved with an optimized dosing regimen. When combined with other strategies to reduce kidney accumulation of scFvs, coadministration of L-lysine has the potential to significantly improve tumour to kidney contrast.
Hamilton
S
S
RAFT Institute of Plastic Surgery, Mount Vernon Hospital, Northwood, Middlesex, HA6 2RN, UK.
Odili
J
J
Wilson
G D
GD
Kupsch
J-M
JM
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism*; D008239:Lysine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008545:Melanoma / Q000473:pathology; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging* / Q000276:immunology; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011509:Proteoglycans / Q000032:analysis / Q000276:immunology*; D016719:Radioimmunodetection; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000951:Antigens, Neoplasm; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D007457:Iodine Radioisotopes; D011509:Proteoglycans; D019275:Radiopharmaceuticals; C069150:melanoma-associated proteoglycan antigen, human; D008239:Lysine