The potential for enhanced tumour localisation by poly(ethylene glycol) modification of anti-CEA antibody.
Attachment of poly(ethylene glycol) (PEG) to proteins can greatly alter their pharmacological properties, including extending the plasma half-life and reducing immunogenicity, both of which are potentially beneficial to tumour targeting. IgG, F(ab')2 and Fab' fragments of the anti-CEA antibody A5B7 were chemically modified with PEG (M(r) 5,000), labelled with 125I and their pharmacokinetics compared with the unmodified forms in the LS174T colonic xenograft in nude mice. PEG modification of the intact antibody had little effect on biodistribution, although tumour localisation was slightly reduced. In contrast, similar modification of F(ab')2 and Fab'A5B7 significantly prolonged plasma half-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 from the circulation than F(ab')2 (M(r) 100,000), but after PEG attachment their biodistributions converged, while the tumour to blood ratios were reduced and resembled that of the intact antibody. The enhanced tumour accumulation, reduced normal tissue to blood ratios and potentially reduced immunogenicity of fragments after PEG attachment may therefore prove superior to either unmodified fragments or intact antibody for antibody-targeted therapy, although the increased plasma half-life may necessitate the use of a clearance mechanism.
Pedley
R B
RB
Department of Clinical Oncology, Royal Free Hospital School of Medicine, London, U.K.
Boden
J A
JA
Boden
R
R
Begent
R H
RH
Turner
A
A
Haines
A M
AM
King
D J
DJ
D000230:Adenocarcinoma / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000737:chemistry; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D011092:Polyethylene Glycols