Determinants of the antitumor effect of radiolabeled monoclonal antibodies.
The murine B-cell lymphoma 38C13 model was used to study the radiobiological effect of 131I-monoclonal antibody (MAB) therapy compared with dose equivalent external beam irradiation. Continuous exponentially decreasing low dose rate (LDR) gamma-irradiation, and multiply fractionated (MF) X-irradiation were compared with dose equivalent 131I-MAB. The relative therapeutic efficacy of radioimmunotherapy, and the relative contribution of (a) low dose rate; (b) whole body irradiation; and (c) microdosimetry to the overall effect were determined. Groups of mice with or without B-cell lymphoma were treated with either (a) 131I-anti-idiotype MAB; (b) 131I-isotype-matched irrelevant control MAB; (c) 5-15 Gy 250 kV X-irradiation given as a single fraction; (d) 2.5-30 Gy 250 kV X-irradiation given in 10 fractions/2 weeks; or by (e) continuous exponentially decreasing gamma-irradiation via a 137Cs source, which simulated the effective t1/2 of the 131I-MAB. In tumor-free mice the LD50/30 was approximately 10 Gy for MF and LDR external irradiation, and 11-12 Gy for 131I-MAB. However, the effect of these modes of irradiation on tumor size differed significantly. The cumulative percentage of tumor reduction averaged over 12 days was 0.635 +/- 0.055%/Gy for MF, and 1.36 +/- 0.061%/Gy for LDR external irradiation (a relative efficacy factor of 1.63 for LDR irradiation; P = 0.01). Assuming homogeneous body distribution, the tumor reduction effect over 12 days for 131I-MAB was 2.064 +/- 0.133%/Gy for specific, and 1.742 +/- 0.1%/Gy for nonspecific isotype-matched irrelevant 131I-MAB (P = 0.02). When 131I-MAB was compared to LDR external irradiation, the relative efficacy factor was 1.99 (P less than 0.001). In summary, there was a dose rate effect on tumor response, which may in part explain the efficacy of radioimmunotherapy. The additional effect of 131I-MAB on tumor response was only partially explained by the cumulative concentration ratio of 131I-MAB tumor/131I-MAB whole body, which was on average 1.7. This relatively low concentration ratio was partly due to tumor-mediated dehalogenation. Thus, the overall tumor response was a function of the total dose, dose rate, and both the specific and nonspecific distribution of 131I-MAB.
Knox
S J
SJ
Department of Radiation Oncology, Stanford University Medical Center, California 94305.
Levy
R
R
Miller
R A
RA
Uhland
W
W
Schiele
J
J
Ruehl
W
W
Finston
R
R
Day-Lollini
P
P
Goris
M L
ML
D000818:Animals; D000911:Antibodies, Monoclonal / Q000302:isolation & purification / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D002588:Cesium Radioisotopes; D005260:Female; D005720:Gamma Rays; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008223:Lymphoma / Q000276:immunology / Q000532:radiotherapy*; D051379:Mice; D008809:Mice, Inbred C3H; D014018:Tissue Distribution; D014965:X-Rays
D000911:Antibodies, Monoclonal; D002588:Cesium Radioisotopes; D007135:Immunoglobulin Variable Region; D007457:Iodine Radioisotopes