Altered pharmacokinetic and tumour localization properties of Fab' fragments of a murine monoclonal anti-CEA antibody by covalent modification with low molecular weight dextran.
This paper describes the modification of Fab' fragments of ZCE025, a murine monoclonal antibody recognizing carcinoembryonic antigen (CEA), with oxidized dextran of low molecular weight. This modification altered the in vitro and in vivo characteristics of the Fab'. The dextran conjugated fragments exhibited markedly reduced renal uptake and excretion and the prolonged residence time of the Fab' in the vascular compartment. The result was enhanced tumour localization of the derivative compounds compared with underivatized Fab', even though the process of chemical coordination reduced the immunoreactivity of the molecule. The isoelectric point of the molecule was much lower than the unaltered Fab' and previous research has shown this to reduce markedly its potential for inducing a human anti-mouse antibody (HAMA) response. Thus, the conjugation of Fab' fragments with low molecular weight oxidized dextrans can increase the bioavailability of these fragments for tumour localization, while simultaneously reducing their immunogenic potential and renal accumulation problems.
Fagnani
R
R
Division of Therapeutics, Hybritech, Inc., San Diego, California 92196-9006, USA.
Halpern
S
S
Hagan
M
M
D000230:Adenocarcinoma / Q000000981:diagnostic imaging; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001693:Biological Transport, Active; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging; D003911:Dextrans / Q000737:chemistry / Q000493:pharmacokinetics; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008970:Molecular Weight; D009369:Neoplasms / Q000000981:diagnostic imaging*; D016719:Radioimmunodetection; D016499:Radioimmunotherapy; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D003911:Dextrans; D007140:Immunoglobulin Fab Fragments