Comparison of the targeting characteristics of various radioimmunoconjugates for radioimmunotherapy of neuroblastoma: dosimetry calculations incorporating cross-organ beta doses.
To optimize the efficacy of radioimmunotherapy (RIT), the ideal antibody-radioisotope combinations should be used to deliver the highest tumor and the lowest normal tissue doses. In a mouse model, tumor and critical organ-absorbed doses delivered by different radioimmunoconjugates were calculated and compared. We used a Medical Internal Radiation Dosimetry (MIRD)-style mouse dosimetry model that incorporates cross-organ beta doses to make refined estimates of the radiation absorbed dose to tissues. Biodistribution data from neuroblastoma xenografted nude mice were used to estimate tumor, organ and bone marrow absorbed dose values for 90Y-3F8, 131I-3F8 and 131I-F(ab')2 fragments. Immunoreactive fractions of the radiolabeled antibodies were comparable. Although tumor uptake of the radioiodinated and radiometal labeled 3F8 was much higher than that of the radioiodinated F(ab')2 fragments (maximum percent injected dose per gram values were 39.4, 33.2 and 20.1 for 131I-3F8, 90Y-3F8 and 131I-F(ab')2, respectively), tumor to nontumor ratios were higher for radioiodinated fragments (with the exception of tumor to kidney ratio). For the minimum tumor dose necessary for complete ablation, the bone marrow received 195, 278 and 401 cGy for 131I-F(ab')2, 131I-3F8 and 90Y-3F8, respectively. Tumor doses were 50.1, 232 and 992 cGy/MBq for 131I-F(ab')2, 131I-3F8 and 90Y-3F8, respectively. Tumor to bone marrow dose, which is defined as the therapeutic index, was 21.5, 14.7 and 10.4 for 131I-F(ab')2, 131I-3F8 and 90Y-3F8. 131I-F(ab')2 fragments produced the highest therapeutic index but also the lowest tumor dose for radioimmunotherapy. Radiometal conjugated IgG produced the highest tumor dose but also the lowest therapeutic index.
Ugur
O
O
Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Kostakoglu
L
L
Hui
E T
ET
Fisher
D R
DR
Garmestani
K
K
Gansow
O A
OA
Cheung
N K
NK
Larson
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics; D001610:Beta Particles; D001932:Brain Neoplasms / Q000532:radiotherapy*; D002614:Chelating Agents; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007128:Immunoglobulin Fragments / Q000276:immunology; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D014018:Tissue Distribution; D015021:Yttrium Radioisotopes
D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007205:Indium Radioisotopes; D007457:Iodine Radioisotopes; D015021:Yttrium Radioisotopes