Determinants of the Antitumor Effect of Kad iolabeIed Monoclonal Antibodies1

The murine B-cell lymphoma 38C13 model was used to study the radiobiological effect of 13ll-monoclonal antibody (MAB) therapy com pared with dose equivalent external beam irradiation. Continuous expo nentially decreasing low dose rate (LDR) -y-irradiation, and multiply fractionated (MF) \-irradiation were compared with dose equivalent I31IMAH. 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) I3ll-antiidiotype MAB; (b) 131I-isotype-matched irrelevant control MAB; (c) 515 Gy 250 kV X-irradiation given as a single fraction; (d) 2.5-30 Gy 250 kV \-irradiation given in 10 fractions/2 weeks; or by (e) continuous exponentially decreasing -y-irradiation via a ""( s source, which simulated the effective t¡,2of the 131I-MAB. In tumor-free mice the LDso/w was approximately 10 Gy for MF and LDR external irradiation, and 11-12 Gy for 13II-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; /' = 0.01). Assuming homogeneous body distribution, the tumor reduction effect over 12 days for 1311-MABwas 2.064 ±0.133%/Gy for specific, and 1.742 ±0.1%/Gy for nonspecific ¡si»type-matched irrelevant 13II-MAB (P = 0.02). When I3II-MAB was compared to LDR external irradiation, the relative efficacy factor was 1.99 (P < 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 I31I-MAB on tumor response was only partially explained by the cumulative concentration ratio of '"I-M AB luninr/'"!MAB whole body, which was on average 1.7. This relatively low concen tration 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 '" I-M AH.