Preparation, characterisation and tumour targeting of cross-linked divalent and trivalent anti-tumour Fab' fragments

被引:47
作者
Casey, JL [1 ]
King, DJ [1 ]
Chaplin, LC [1 ]
Haines, AMR [1 ]
Pedley, RB [1 ]
Mountain, A [1 ]
Yarranton, GT [1 ]
Begent, RHJ [1 ]
机构
[1] CELLTECH LTD,SLOUGH SL1 4EN,BERKS,ENGLAND
基金
英国医学研究理事会;
关键词
maleimide cross-linking; radioimmunotherapy; di-Fab; tri-Fab;
D O I
10.1038/bjc.1996.555
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The monoclonal anti-CEA antibody, A5B7, has previously been administered to patients for radioimmunotherapy (RIT). Long circulation time and the formation of an immune response have limited therapeutic success in the clinic. Antibody fragments can be used to reduce the in vivo circulation time, but the best combination of fragment and radioisotope to use for therapy is far from clear. In this study we have compared the biodistribution of A5B7 IgG and F(ab')(2) with chemically cross-linked divalent (DFM) and trivalent (TFM) A5B7 Fab' fragments in nude mice bearing human colorectal tumour xenografts. The crosslinkers were designed to allow site-specific labelling using yttrium 90 (Y-90), a high-energy beta-emitter. We have also compared the above antibody forms conjugated to both I-131 and Y-90. Both DFM and TFM were fully immunoreactive and remained intact after radiolabelling and incubation in serum at 37 degrees C for 24 h. Biodistribution results showed similar tumour uptake levels and an identical blood clearance pattern for F(ab')2 and DFM with high tumour-blood ratios generated in each case. However, unacceptably high kidney accumulation for both F(ab')(2) and DFM and elevated splenic uptake of DFM labelled with Y-90 was observed. Kinetic analysis of antigen binding revealed that DFM had the fastest association rate (k(ass) = 1.6 x 10(5) Ms(-1)) of the antibody forms, perhaps owing to increased flexibility of the cross-linker. This advantage implies that DFM may be more suitable than F(ab')(2) radiolabelled with I-131 for RIT. TFM cleared from the blood significantly faster than A5B7 IgG when labelled with both I-131 and Y-90, producing an improved therapeutic tumour-blood ratio. Kidney accumulation was not observed for [Y-90]TFM, but a slightly higher splenic uptake was observed that may indicate reticuloendothelial system (RES) uptake. Overall, tumour uptake was higher for Y-90-labelled antibodies than for I-131-labelled antibodies. Because of the faster clearance, it should be possible to administer a higher total dose of Y-90-labelled TFM than IgG, which is attractive for RIT. Both A5B7 DFM and TFM, therefore, show favourable properties compared with their parent antibody forms.
引用
收藏
页码:1397 / 1405
页数:9
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