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Rivista di Medicina Nucleare e Imaging Molecolare

A Journal on Nuclear Medicine and Molecular Imaging
Affiliated to the Society of Radiopharmaceutical Sciences and to the International Research Group of Immunoscintigraphy
Indexed/Abstracted in: Current Contents/Clinical Medicine, EMBASE, PubMed/MEDLINE, Science Citation Index (SciSearch), Scopus
Impact Factor 2,413

Periodicità: Trimestrale

ISSN 1824-4785

Online ISSN 1827-1936


The Quarterly Journal of Nuclear Medicine 1998 Dicembre;42(4):225-41


Pharmacokinetics and bio­dis­trib­u­tion of genet­i­cal­ly-engi­neered anti­bod­ies

Colcher D.*, Pavlinkova G., Beresford G., Booth B. J. M., Choudhury A., Batra S. K.

From the Department of Pathology and Microbiology [DC, GP, GB, ­BJMB] and Department of Biochemistry and Molecular Biology [AC, SKB] University of Nebraska Medical Center, Omaha, Nebrasca, USA

Monoclonal anti­bod­ies (MAbs), ­because of ­their inher­ent spec­i­fic­ity, are ­ideal tar­get­ing ­agents. They can be ­used to deliv­er radio­nu­clides, tox­ins or cyto­tox­ic ­drugs to a spe­cif­ic tis­sue or malig­nant ­cell pop­u­la­tions. Intact immu­no­glob­u­lin (IgG) mole­cules ­have sev­er­al prac­ti­cal lim­i­ta­tions of ­their phar­ma­col­o­gy; ­their rel­a­tive­ly ­large ­size of approx­i­mate­ly 150,000 dal­tons ­leads to a ­slow clear­ance ­from the ­blood ­pool and the ­body result­ing in sig­nif­i­cant expo­sure to nor­mal ­organs ­with lim­it­ed quan­tities deliv­ered to ­tumors. The IgG mole­cule ­shows a rel­a­tive­ly ­poor dif­fu­sion ­from the vas­cu­la­ture ­into and ­through the ­tumor. Attempts to mod­i­fy the phar­ma­col­o­gy of the Ig mole­cule ­have clas­si­cal­ly ­involved the use of pro­teas­es to gen­er­ate F(ab’)2 and Fab’ frag­ments ­with molec­u­lar ­weights of ≈100,000 and 50,000 dal­tons, respec­tive­ly. Fv frag­ments of IgG are one of the small­est ­size func­tion­al mod­ules of anti­bod­ies ­that ­retain ­high affin­ity bind­ing of an anti­gen. Their small­er ­size, ≈25,000 dal­tons, ­enables bet­ter ­tumor pen­e­tra­tion and ­makes ­them poten­tial­ly ­more use­ful ­than a ­whole anti­body mole­cule for clin­i­cal appli­ca­tions. Molecular clon­ing and expres­sion of the var­i­able ­region ­genes of IgG has great­ly facil­i­tat­ed the gen­er­a­tion of engi­neered anti­bod­ies. A sin­gle-­chain Fv (scFv) recom­bi­nant pro­tein, pre­pared by con­nect­ing ­genes encod­ing for ­heavy-­chain and ­light-­chain var­i­able ­regions at the DNA lev­el by an appro­pri­ate oli­go­nu­cleo­tide link­er, ­clears ­from the ­blood at ­much fast­er ­rate ­than ­intact IgG. The scFv frag­ment can ­retain an anti­gen-bind­ing affin­ity sim­i­lar to ­that of a monov­al­ent Fab’ frag­ment; ­this how­ev­er, rep­re­sents a rel­a­tive ­decrease in bind­ing affin­ity ­when com­pared to ­intact anti­bod­ies. The scFv ­with its fast­er clear­ance and low­er affin­ity ­results in a low­er per­cent-inject­ed ­dose local­iz­ing in ­tumors ­when com­pared to the diva­lent IgG mole­cule. This may be ade­quate for imag­ing but prob­ably not for ther­a­py. The valen­cy of the MAb frag­ment is crit­i­cal for the func­tion­al affin­ity of an anti­body to a ­cell sur­face or a poly­mer­ic anti­gen. In ­attempts to gen­er­ate mul­ti­va­lent ­forms of scFv mole­cules, non-cova­lent­ly ­linked scFv dimer­ic and tri­mer­ic mole­cules, dis­ul­fide ­linked dimer­ic scFvs, as ­well as cova­lent­ly ­linked chi­mer­ic scFvs ­have ­been stud­ied. These mul­ti­va­lent scFvs gen­er­al­ly ­have a high­er func­tion­al affin­ity ­than the monov­al­ent ­form result­ing in bet­ter in ­vivo tar­get­ing. Another way to ­alter the phar­ma­col­o­gy of the scFvs is to mod­i­fy its net ­charge. Charge-mod­i­fied scFvs ­with ­desired iso­electric ­points (pI), ­have ­been pre­pared by insert­ing neg­a­tive­ly ­charged ami­no ­acids on the tem­plate of the var­i­able ­region ­genes. This can ­help to over­come unde­sir­able ele­va­tions in ­renal ­uptake ­seen ­with ­most anti­body frag­ments. In con­clu­sion, genet­ic manip­u­la­tions of the immu­no­glob­u­lin mole­cules are effec­tive ­means of alter­ing stabil­ity, func­tion­al affin­ity, phar­ma­cok­i­net­ics, and bio­dis­trib­u­tion of the anti­bod­ies ­required for the gen­er­a­tion of the “mag­ic ­bullet”.

lingua: Inglese


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