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Determinants of the Antitumor Effect of Radiolabeled Monoclonal Antibodies¹

Departments of Radiation Oncology [S. J. K.], Medicine/Division of Medical Oncology [R. L.], Pathology [W. R.], Diagnostic Radiology and Nuclear Medicine [M. L. G.], Stanford University Medical Center, Stanford California 94305; Division of Laboratory Animal Medicine [J. S., P. D-L.], Department of Health Physics [R. F.], Stanford University, Stanford, California 94305; IDEC Pharmaceuticals Corporation [R. A. M., W. U.], Mountain View, California 94043

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) -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 -irradiation via a ¹³⁷Cs source, which simulated the effective t_1/2 of the ¹³¹I-MAB. In tumor-free mice the LD_50/30 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 < 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.

¹ This work was partially supported by an American Cancer Society grant, NIH Grants CA33399, CA34233, and RR0362403, and a gift from The Friends of Radiology. R. L. is an American Cancer Society Clinical Research Professor.

² Present address: Cytogen Corporation, Princeton, NJ 08540.

Received 1/ 8/90. Revised 5/ 7/90.

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