Tumour targeting of humanised cross-linked divalent-Fab' antibody fragments: a clinical phase I/II study.
Antibody engineering has made it possible to design antibodies with optimal characteristics for delivery of radionuclides for tumour imaging and therapy. A humanised divalent-Fab' cross-linked with a bis-maleimide linker referred to as humanised divalent-Fab' maleimide was produced as a result of this design process. It is a humanised divalent antibody with no Fc, which can be produced in bacteria and has enhanced stability compared with F(ab')(2). Here we describe a clinical study in patients with colorectal cancer using humanised divalent-Fab' maleimide generated from the anti-carcinoembryonic antigen antibody A5B7 radiolabelled with iodine-131. Ten patients received an i.v. injection of iodine-131-labelled A5B7 humanised divalent-Fab' maleimide, and positive tumour images were obtained by gamma camera imaging in eight patients with known lesions, and one previously undetected lesion was identified. True negative results were obtained in two patients without tumour. Area under the curve analysis of serial blood gamma counting and gamma camera images showed a higher tumour to blood ratio compared to A5B7 mF(ab')(2) used previously in the clinic, implying this new molecule may be superior for radioimmunotherapy. MIRD dose calculations showed a relatively high radiation dose to the kidney, which may limit the amount of activity that could be administered in radioimmunotherapy. However the reduction in immunogenicity was also a major advantage for A5B7 humanised divalent-Fab' maleimide over murine versions of this antibody suggesting that humanised divalent-Fab' maleimide should be a useful vehicle for repeated therapies.
Casey
J L
JL
Cancer Research UK Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
Napier
M P
MP
King
D J
DJ
Pedley
R B
RB
Chaplin
L C
LC
Weir
N
N
Skelton
L
L
Green
A J
AJ
Hope-Stone
L D
LD
Yarranton
G T
GT
Begent
R H J
RH
D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D008301:Maleimides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016499:Radioimmunotherapy / Q000379:methods; D011877:Radionuclide Imaging
D007140:Immunoglobulin Fab Fragments; D008301:Maleimides; C043592:maleimide