Structure-function relationships in indium-111 radioimmunoconjugates.
Conjugates formed by reaction of monoclonal antibody B72.3 with benzyl isothiocyanate derivatives of four amino polycarboxylate chelators (NTA, EGTA, EDTA, DTPA) were labeled with indium-111 and administered iv to athymic mice bearing antigen-positive (LS174T) and antigen-negative (A375) human tumor xenografts. Conjugate immunoreactivities, antibody dose, and xenograft size were controlled, so that the effects of varying chelate structure could be evaluated under conditions where immunological and physiological factors were effectively held constant. Tissue distribution and excretion of the radiometal at 24 and 48 h postinjection were shown to correlate directly with chelate thermodynamic stability (NTA less than EGTA less than EDTA less than DPTA). Radioactivity levels in the blood and the LS174T xenograft increased, while kidney levels and excretion levels decreased, with increasing chelate stability. The kidney was the only normal organ that accumulated non-antibody-bound 111In, uptake of radioactivity into all other tissues, and in particular the liver, being unaffected by changes in chelate structure. Mean transferrin saturation in the tumor-bearing athymic mice was found to be 65%. It is proposed that uptake of free 111In by serum transferrin is precluded in this model, leading to the observed renal localization of unbound label. Kidney:blood and kidney:LS174T activity ratios at 48 h postinjection provided the most sensitive indices of conjugate instability in vivo, spanning 50- and 20-fold ranges, respectively, between the least stable and the most stable conjugate. It is concluded that this antigen/antibody system and mouse model are well-suited to structure-function studies of immunoglobulin labels.
Brandt
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KD
Abbott Laboratories, Department 90M, Abbott Park, Illinois 60064.
Johnson
D K
DK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry*; D004492:Edetic Acid / Q000737:chemistry; D004533:Egtazic Acid / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007205:Indium Radioisotopes / Q000032:analysis* / Q000737:chemistry; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000378:metabolism; D009571:Nitrilotriacetic Acid / Q000737:chemistry; D004369:Pentetic Acid / Q000737:chemistry; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014168:Transferrin / Q000032:analysis; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D007205:Indium Radioisotopes; D014168:Transferrin; D004533:Egtazic Acid; D004369:Pentetic Acid; D004492:Edetic Acid; D009571:Nitrilotriacetic Acid