Preparation and preclinical assessment of folate-conjugated, radiolabelled antibodies.
BACKGROUND
The folate receptor (FR) is frequently over-expressed on human cancer cells and may be a suitable target for radiopharmaceuticals. Because of FR expression in the kidneys, the rapidly renal clearing folate is not well suited as a carrier for therapeutic radionuclides. As an alternative, folate-immunoglobulin conjugates were studied as potential carriers for radionuclides.


METHODS
Two types of conjugate were evaluated: (i) folate conjugated to osteosarcoma antigen directed murine monoclonal antibodies TP-1 and TP-3 or (ii) folate conjugated to non-specific polyclonal human IgG (HIg6). These constructs were labelled with 211At or 125I.


RESULTS
The folate-HIg6-radionuclide conjugate showed high affinity to immobilized folate binding protein and also to folate receptor-expressing cells. Folate conjugates of TP-1 and TP-3 had a selective binding in vitro to antigen-expressing tumor cells and also to cells expressing FR only, thus the folate antibody constructs possessed dual affinity binding. Comparisons between folate-conjugated and non-folated antibody in Balb/C mice showed that the folate did not markedly change the properties of the radiolabelled antibody.


CONCLUSIONS
It was demonstrated that folate-conjugated antibodies carrying therapeutic radionuclides have relevant properties for the targeting of tumor cells expressing FR.
Henriksen
Gjermund
G
Department of Chemistry, University of Oslo, Blindern N-0315 Oslo, Norway.
Bruland
Oyvind S
OS
Larsen
Roy H
RH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D000951:Antigens, Neoplasm / Q000276:immunology; D001246:Astatine / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D012516:Osteosarcoma / Q000276:immunology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000276:immunology / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium / Q000737:chemistry
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D018796:Immunoconjugates; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; D014316:Tritium; D005492:Folic Acid; D001246:Astatine