Dosimetric evaluation and radioimmunotherapy of anti-tumour multivalent Fab' fragments

We have been investigating the use of cross-linked divalent (DFM) and triva lent (TFM) versions of the anti-carcinoembryonic antigen (CEA) monoclonal a ntibody A5B7 as possible alternatives to the parent forms (IgG and F(ab')(2 )) which have been used previously in clinical radioimmunotherapy (RIT) stu dies in colorectal carcinoma, Comparative biodistribution studies of simila r sized DFM and F(ab), and TFM and IgG, radiolabeled with both I-131 and Y- 90 have been described previously using the human colorectal tumour LS174T nude mouse xenograft model (Casey et al (1996) Br J Cancer 74: 1397-1405). in this study quantitative estimates of radiation distribution and RIT in t he xenograft model provided more insight into selecting the most suitable c ombination for future RIT. Radiation doses were significantly higher in all tissues when antibodies were labelled with Y-90. Major contributing organs were the kidneys, liver and spleen, The extremely high absorbed dose to th e kidneys on injection of Y-90-labelled DFM and F(ab')(2), as a result of a ccumulation of the radiometal would result in extremely high toxicity. Thes e combinations are clearly unsuitable for RIT, Cumulative dose of Y-90-TFM to the kidney was 3 times lower than the divalent forms but still twice as high as for Y-90-IgG. TFM clears faster from the blood than IgG, producing higher tumour to blood ratios. Therefore when considering only the tumour t o blood ratios or the total absorbed dose, the data suggests that TFM would be the most suitable candidate. However, when corrected for equitoxic bloo d levels, doses to normal tissues for TFM were approximately twice the leve l of IgG, producing a two-fold increase in the overall tumour to normal tis sue ratio. In addition RIT revealed that for a similar level of toxicity an d half the administered activity, Y-90-IgG produced a greater therapeutic r esponse. This suggests that the most promising A5B7 antibody form with the radionuclide Y-90 may be IgG. Dosimetry analysis revealed that the tumour t o normal tissue ratios were greater for all I-131-labelled antibodies. This suggests that I-131 may be a more suitable radionuclide for RIT, in terms of lower toxicity to normal tissues. The highest tumour to blood dose and t umour to normal tissue ratio at equitoxic brood levels was I-131-labelled D FM, suggesting that I-131-DFM may be best combination of antibody and radio nuclide for A5B7. The dosimetry estimates were in agreement with RIT result s in that twice the activity of I-131-DFM must be administered to produce a similar therapeutic effect as I-131-TFM. The toxicity in this therapy expe riment was minimal and further experiments at higher doses are required to observe if there would be any advantage of a higher initial dose rate for I -131-DFM. (C) 1999 Cancer Research Campaign.