Antibody and radionuclide characteristics and the enhancement of the effectiveness of radioimmunotherapy by selective dose delivery to radiosensitive areas of tumour.
OBJECTIVE
Estimating the absorbed dose to tumour relative to normal tissues has often been used in the assessment of the therapeutic efficacy of radiolabelled antibodies for radioimmunotherapy. Typically, the calculations assume a uniform dose deposition and response throughout the tumour. However, the heterogeneity of the dose delivery and response within tumours can lead to a radiobiological effect inconsistent with dose estimates. The aim was to assess the influence of antibody and radionuclide characteristics on the heterogeneity of dose deposition.


METHODS
Quantitative images of the temporal and spatial heterogeneity of a range of antibodies in tumour were acquired using radioluminography. Subsequent registration with images of tumour morphology then allowed the delineation of viable and necrotic areas of tumour and the measurement of the antibody concentration in each area. A tumour dosimetry model then estimated the absorbed dose from 131I and 90Y in each area.


RESULTS
Tumour-specific antibodies initially localized in the viable radiosensitive areas of tumour and then penetrated further into tumour with continued tumour accretion. Multivalent antibodies were retained longer and at higher concentrations in viable areas, while monovalent antibodies had greater mobility. In contrast, non-specific antibodies penetrated into necrotic regions regardless of their size. As a result, multivalent, specific antibodies delivered a significantly larger dose to viable cells compared with monovalent antibodies, while non-specific antibodies deposited most of the dose in necrotic areas. There was a significant difference in dose estimates when assuming a uniform dose deposition and accounting for heterogeneity. The dose to the viable and necrotic areas also depended on the properties of the radionuclide where antibodies labelled with 131I generally delivered a higher dose throughout the tumour even though the instantaneous dose-rate distribution for 90Y was more uniform.


CONCLUSIONS
The extent of heterogeneity of dose deposition in tumour is highly dependent on the antibody characteristics and radionuclide properties, and can enhance therapeutic efficacy through the selective dose delivery to the radiosensitive areas of tumour.
Flynn
A A
AA
CRC Targeting and Imaging Group, Department of Clinical Oncology, Royal Free and University College Medical School, Royal Free Campus, University College London, London NW3 2PF, UK. a.flynn@ucl.ac.uk
Pedley
R B
RB
Green
A J
AJ
Boxer
G M
GM
Boden
R
R
Bhatia
J
J
Morris
R
R
Begent
R H J
RH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011836:Radiation Tolerance; D016499:Radioimmunotherapy / Q000379:methods*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes