Evaluation of indium-111- and yttrium-90-labeled linker-immunoconjugates in nude mice and dogs.
Rapid uptake and slow transit of radioactivity from normal organs are detrimental to any clinical utilized radioimmunoconjugate because they lower the target-to-nontarget ratio and deliver undesirable radiation to normal organs. To mitigate this problem, two labile chemical linkages (EGS and DST) were introduced between a monoclonal antiferritin antibody (QCI) and a chelating agent (DTPA). The biodistribution of labile-linker immunoconjugates (EGS and DST) and stable linker immunoconjugates (DSS and ITCB) were compared. In a nude mouse model, all of the four immunoconjugates labeled with 111In targeted subcutaneously-implanted human tumor cells. Tumor-to-normal organ ratios were enhanced for the EGS linkage in comparison to the two stable linkages. Serial whole-body immunoscintigraphy confirmed the biodistribution study. The EGS and ITCB 90Y-labeled immunoconjugates had biodistributions similar to their respective 111In-labeled immunoconjugates. As the mouse model is not representative of the high uptake of monoclonal antibodies in the human liver, beagle dogs were used to further explore the retention of radiolabel in normal liver. The EGS-linked immunoconjugate significantly reduced the dog liver activity when compared to the ITCB immunoconjugate. The combination of the animal models (mouse and dog) appears to allow for a more compete and optimal preclinical analysis of chelated radiolabeled monoclonal antibodies for diagnosis or treatment and illustrates the potential clinical improvements possible with labile chemical linkages in radioimmunoconjugates.
Department of Radiotherapy, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
S M
SM
Quadri
H M
HM
Vriesendorp
P K
PK
Leichner
J R
JR
Williams
D000818:Animals; D003432:Cross-Linking Reagents; D004285:Dogs; D005260:Female; D007205:Indium Radioisotopes; D051379:Mice; D008819:Mice, Nude; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes
D003432:Cross-Linking Reagents; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes