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The Quarterly Journal of Nuclear Medicine 2000 September;44(3):268-83

Copyright © 2009 EDIZIONI MINERVA MEDICA

lingua: Inglese

Designer genes: recombinant antibody fragments for biological imaging

Wu A. M., Yazaki P. J.

From the Department of Molecular Biology Beckman Research Institute of the City of Hope, Duarte, CA


FULL TEXT  


Monoclonal anti­bod­ies (MAbs), ­with ­high spe­cif­i­cy and ­high affin­ity for ­their tar­get anti­gens, can be uti­lized for deliv­ery of ­agents ­such as radio­nu­clides, ­enzymes, ­drugs, or tox­ins in ­vivo. However, the imple­men­ta­tion of radio­lab­eled anti­bod­ies as “mag­ic bul­lets” for detec­tion and treat­ment of dis­eas­es ­such as can­cer has ­required address­ing sev­er­al short­com­ings of ­murine MAbs. These ­include ­their immu­nog­e­nic­ity, sub-opti­mal tar­get­ing and phar­ma­cok­i­net­ic prop­er­ties, and prac­ti­cal ­issues of pro­duc­tion and radio­lab­el­ing. Genetic engi­neer­ing pro­vides a pow­er­ful ­approach for rede­sign­ing anti­bod­ies for use in onco­log­ic appli­ca­tions in ­vivo. Recombinant frag­ments ­have ­been pro­duced ­that ­retain ­high affin­ity for tar­get anti­gens, and dis­play a com­bi­na­tion of rap­id, ­high-lev­el ­tumor tar­get­ing ­with con­com­i­tant clear­ance ­from nor­mal tis­sues and the cir­cu­la­tion in ani­mal mod­els. An impor­tant ­first ­step was clon­ing and engi­neer­ing of anti­body ­heavy and ­light ­chain var­i­able ­domains ­into sin­gle-­chain Fvs (molec­u­lar ­weight, 25-27 kDa), in ­which the var­i­able ­regions are ­joined via a syn­thet­ic link­er pep­tide ­sequence. Although scFvs them­selves ­showed lim­it­ed ­tumor ­uptake in preclin­i­cal and clin­i­cal stud­ies, ­they pro­vide a use­ful build­ing ­block for inter­me­di­ate-­sized recom­bi­nant frag­ments. Covalently ­linked dim­ers or non-cova­lent dim­ers of scFvs (­also ­known as dia­bod­ies) ­show ­improved tar­get­ing and clear­ance prop­er­ties due to ­their high­er molec­u­lar ­weight (55 kDa) and ­increased avid­ity. Further ­gains can be ­made by gen­er­a­tion of larg­er recom­bi­nant frag­ments, ­such as the min­i­body, an scFv-CH3 ­fusion pro­tein ­that ­self-assem­bles ­into a biva­lent dim­er of 80 kDa. A system­at­ic eval­u­a­tion of scFv, dia­body, min­i­body, and ­intact anti­body (­based on com­par­i­son of ­tumor ­uptakes, ­tumor:­blood activ­ity ­ratios, and cal­cu­la­tion of an Imaging Figure of Merit) can ­form the ­basis for selec­tion of com­bi­na­tions of recom­bi­nant frag­ments and radio­nu­clides for imag­ing appli­ca­tions. Ease of engi­neer­ing and expres­sion, com­bined ­with nov­el spec­i­fic­ities ­that ­will ­arise ­from advanc­es in genom­ic and com­bin­a­to­ri­al approach­es to tar­get dis­cov­ery, ­will ush­er in a new era of recom­bi­nant anti­bod­ies for bio­log­i­cal imag­ing.

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