Biodistribution of anti-CEA F(ab')2 fragments conjugated with chelating polymers: influence of conjugate electron charge on tumor uptake and blood clearance.
F(ab')2 fragments of anti-carcinoembryonic antigen (CEA) monoclonal antibody (mAb) were modified with three chain-terminal polylysine-based chelating polymers so as to carry different electron charges. Immunoreactive conjugates labeled with 111In up to a specific radioactivity of 120-140 microCi/micrograms were injected into nude mice bearing human colorectal carcinoma, and the biodistribution patterns were compared with each other and with that of an anti-CEA F(ab')2-DTPA control. Immunoconjugate modified with positively-charged polymer produced the highest tumor uptake [up to 20% injected dose per gram (ID/g)], with very significant non-specific radioactivity in normal organs (particularly kidneys). When modified with a polymer carrying only a slight negative charge, the immunoconjugate also produced fairly high tumor uptake (up to 18% ID/g), with much lower non-specific radioactivity in normal organs. Highly negatively-charged conjugate produced the lowest tumor uptake (up to 8% ID/g), whereas blood and whole-body clearances were the fastest but slower than those of conventionally labeled F(ab')2 mAb. The possible mechanisms for the effects described are discussed.
Slinkin
M A
MA
Laboratoire Biophysique-Cancerologie, INSERM U.211, Plateau Technique CHR, Nantes, France.
Curtet
C
C
Faivre-Chauvet
A
A
Sai-Maurel
C
C
Gestin
J F
JF
Torchilin
V P
VP
Chatal
J F
JF
D000230:Adenocarcinoma / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000032:analysis / Q000378:metabolism; D001665:Binding Sites; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002852:Chromatography, Ion Exchange; D003110:Colonic Neoplasms / Q000097:blood / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000737:chemistry / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000378:metabolism*; D000922:Immunotoxins / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D007205:Indium Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011108:Polymers / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D013388:Succinimides / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000888:Antibodies, Anti-Idiotypic; D002272:Carcinoembryonic Antigen; D002614:Chelating Agents; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D007205:Indium Radioisotopes; D011108:Polymers; D013388:Succinimides; D004295:Dihydroxyphenylalanine; C042424:succinimidyl 4-(4-maleimidophenyl)butyrate