Differential metabolic patterns of iodinated versus radiometal chelated anticarcinoma single-chain Fv molecules.
Genetically engineered single-chain Fvs (sFv) are defined as recombinant proteins composed of a variable light chain amino acid sequence of an immunoglobulin tethered to a variable heavy chain sequence by a designed peptide. Previous studies using iodine-labeled sFv, derived from the anticarcinoma monoclonal antibody CC49, showed that the 125I-sFv could efficiently target antigen-positive tumors in a human tumor xenograft model while demonstrating rapid plasma clearance and minimal uptake in normal organs. One of the issues we raised in the analysis of the iodinated sFv metabolic studies was whether similar metabolic patterns would be observed if the sFv were labeled with a radiometal. In the studies reported here, 125I-CC49 sFv and 177Lu-CC49 sFv were co-injected in mice bearing antigen-positive carcinoma xenografts. Both sFv forms showed similar tumor targeting and plasma clearance pharmacokinetics. The 177Lu-sFv, however, showed a greater uptake in liver and spleen and a much higher uptake in kidney. These studies thus demonstrate that despite their small size (M(r) 27,000), the metal-chelated sFv shows a metabolic pattern very different than that of the iodinated sFv, which is most likely due to retention of the metal by organs metabolizing the sFv.
Schott
M E
ME
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Milenic
D E
DE
Yokota
T
T
Whitlow
M
M
Wood
J F
JF
Fordyce
W A
WA
Cheng
R C
RC
Schlom
J
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002614:Chelating Agents / Q000378:metabolism / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000378:metabolism; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000378:metabolism; D007147:Immunoglobulin Light Chains / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000378:metabolism; D007457:Iodine Radioisotopes; D008187:Lutetium; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011868:Radioisotopes; D011994:Recombinant Proteins / Q000378:metabolism; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D007457:Iodine Radioisotopes; D009363:Neoplasm Proteins; D011868:Radioisotopes; D011994:Recombinant Proteins; D008187:Lutetium