THE POTENTIAL FOR ENHANCED TUMOR-LOCALIZATION BY POLY(ETHYLENE GLYCOL) MODIFICATION OF ANTI-CEA ANTIBODY

Attachment of poly(ethylene glycol) (PEG) to proteins can greatly alte r their pharmacological properties, including extending the plasma hal f-life and reducing immunogenicity, both of which are potentially bene ficial to tumour targeting. IgG, F(ab')(2) and Fab' fragments of the a nti-CEA antibody A5B7 were chemically modified with PEG (M(r) 5,000), labelled with I-125 and their pharmacokinetics compared with the unmod ified forms in the LS174T colonic xenograft in nude mice. PEG modifica tion of the intact antibody had little effect on biodistribution, alth ough tumour localisation was slightly reduced. In contrast, similar mo dification of F(ab')(2) and Fab'A5B7 significantly prolonged plasma ha lf-life and increased radioantibody accumulation in the tumour and to a lesser extent in normal tissues, but reduced tissue to blood ratios. Prior to modification, Fab' A5B7 (M(r) 50,000) cleared more rapidly f rom the circulation than F(ab')(2) (M(r) 100,000), bur after PEG attac hment their biodistributions converged, while the tumour to blood rati os were reduced and resembled that of the intact antibody. The enhance d tumour accumulation, reduced normal tissue to blood ratios and poten tially reduced immunogenicity of fragments after PEG attachment may th erefore prove superior to either unmodified fragments or intact antibo dy for antibody-targeted therapy, although the increased plasma half-l ife may necessitate the use of a clearance mechanism.