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  MOLECULAR MANIPULATION AND PHARMACOKINETICS 

The Quarterly Journal of Nuclear Medicine 1998 December;42(4):250-61

Copyright © 2000 EDIZIONI MINERVA MEDICA

language: English

Effects of linker chemistry on the pharmacokinetics of radioimmunoconjugates

Quadri S. M., Vriesendorp H. M.*

From the Center for Scientific Review, National Institutes of Health, Bethesda, Maryland * Arlington Cancer Center, Arlington, Texas, USA


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Radiolabeled mono­clo­nal anti­bod­ies reac­tive ­with ­tumor-asso­ciat­ed anti­gens can selec­tive­ly deliv­er cyto­tox­ic or diag­nos­tic iso­topes to malig­nant ­cells in ­vivo. To ­achieve max­i­mum reten­tion of radio­lab­el in ­tumor and a ­more rap­id clear­ance of radio­iso­tope ­from nor­mal tis­sues, six link­er immu­no­con­ju­gates ­were eval­u­at­ed in stud­ies ­using ­nude ­mice and bea­gle ­dogs. All radio­im­mu­no­con­ju­gates con­tained a ­mouse mono­clo­nal IgG (QCI) reac­tive ­with ­human fer­ri­tin. Different chem­i­cal link­ag­es ­were insert­ed ­between immu­no­glob­u­lins and the radio­lab­eled che­late (­DTPA). Three link­ers ­(­ITCB, DSS and BSO­COES) were ­stable in in ­vitro and in ­vivo studies. Three link­ers ­ (EGS, DST and DSP) were ­labile in in ­vitro and in ­vivo studies. Indium-111 ­labeled anti­fer­rit­in-con­tain­ing ­ITCB or DSS ­linker showed ­high ­uptake in ­human hepat­o­ma xen­o­grafts in ­nude ­mice. In addi­tion, ­long ­blood ­half-­lives and high­er nor­mal liv­er ­uptakes ­were not­ed. Studies of ­whole ­body reten­tion of radio­im­mu­no­con­ju­gates ­showed approx­i­mate­ly ­three-­fold fast­er elim­i­na­tion of radio­im­mu­no­con­ju­gates con­tain­ing a ­labile link­er (EGS). EGS link­er is the ­labile link­er ­with the high­est ther­a­peu­tic ­ratio: high­er ­tumor ­uptake, but low nor­mal liv­er ­uptake and a short­ened ­blood ­half-­life of the radio­im­mu­no­con­ju­gate. The differences in normal tissue uptake (liver) between EGS and ITCB were confirmed in beagle dogs. Urine elim­i­na­tion stud­ies and incu­ba­tion of radio­im­mu­no­con­ju­gates in ser­um or tis­sue homog­en­ates of ­tumor, liv­er or mus­cle, ­showed ­that ­enzymes in ser­um and liv­er homog­en­ates ­were ­able to ­cleave the ­labile link­ers, ­which led to a ­more rap­id elim­i­na­tion of low molec­u­lar ­weight radio­ac­tive metab­olites in ­urine. The metab­olism of link­er radio­im­mu­no­con­ju­gates in ­tumor was ­less effec­tive. The ­labile link­er DSP ­appears ­less use­ful because sulf­phy­dryl ­groups ­that are gen­er­at­ed by cleav­age ­of cause high­er ­uptake radioactivity in nor­mal kid­ney. Biodistribution stud­ies in ­nude ­mice ­were con­firmed by seri­al immu­nos­cin­tig­ra­phy stud­ies on indi­vid­u­al ­mice. The immu­nos­cin­tig­ra­phy stud­ies are ­semi-quan­ti­ta­tive ­only, but ­enable the use of low­er num­bers of experi­men­tal ani­mals. This is of particular significance in large experimental animals such as beagle dogs. The ­labile link­er ­approach can ­reduce nor­mal tis­sue radi­a­tion expo­sure. The ­study ­also pro­vides an exam­ple of pre­clin­i­cal opti­mi­za­tion of radio­im­mu­no­con­ju­gates. Continued use of the appro­pri­ate pre­clin­i­cal ani­mal mod­els ­will accel­er­ate ­more suc­cess­ful appli­ca­tions of radio­im­mu­no­con­ju­gates in can­cer ­patients.

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