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


language: English

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


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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