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Immunospecific Saturable Clearance Mechanisms for Indium-111-labeled Anti-Melanoma Monoclonal Antibody 96.5 in Humans¹

Departments of Clinical Immunology and Biological Therapy [J. L. M., L. J. S., M. E. B., M. G. R.], Nuclear Medicine [L. M. L.], and Medical Oncology [C. E. P., R. S. B.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Hybritech, Incorporated, San Diego, California 92126-9990 [S. S., M. W. U.]

Liver uptake of ¹¹¹In-labeled monoclonal antibodies (MoAb) remains a significant problem in radioimaging studies to date. To determine if the observed liver uptake of an ¹¹¹In-labeled anti-melanoma antibody 96.5 (¹¹¹In-96.5) was dependent on the presence of hepatic antigen or on recognition of circulating murine antibody, escalating doses of an unlabeled nonimmunoreactive MoAb (NIR-MoAb) were administered to 18 patients with metastatic malignant melanoma either 1 or 24 h prior to an infusion of 1 mg of ¹¹¹In-96.5. The number of metastases imaged, pharmacokinetics, and the ratio of radioactivity (expressed as average counts/pixel) in liver (L), spleen (S), bone (B), and kidney (K) compared to blood pool (heart = H) were examined. Results were prospectively compared with data from six patients who received immunoreactive unlabeled 96.5 prior to ¹¹¹In-96.5. Increasing dose or changes in the preinfusion time of NIR-MoAb had no significant effect on the biodistribution of ¹¹¹In-96.5. In contrast, patients who received unlabeled, immunoreactive 96.5 prior to ¹¹¹In-96.5 infusion demonstrated a significant drop [P < 0.001] in the liver/heart ratio of radioactivity [2.81 ± 0.35 (SEM)] compared to patients receiving the identical dose of NIR-MoAb [10.35 ± 1.33]. Significant decreases in spleen/heart and bone/heart ratios were also observed. Pharmacokinetic studies showed that the volume of distribution (V_d) and the plasma t, both decreased when 96.5 was administered compared to NIR-MoAb. In addition, a 4-fold increase in concentration x time was obtained after 96.5 antibody was administered compared to NIR-MoAb. More metastases were imaged in patients receiving preinfusions of 96.5 (23 of 28) than in patients receiving NIR-MoAb (10 of 18; P < 0.05). Although tissue distribution of ¹¹¹In-labeled antibody can be ascribed to nonspecific organ clearance of murine antibodies, a substantial component of tissue disposition of antibody 96.5 was shown to be a consequence of specific clearance of immunoreactive antibody which may cross-react with tissue antigens.

¹ Work was supported in part by Hybritech, Incorporated. Work was presented in part at the American Association for Cancer Research, May 1987.

² To whom requests for reprints should be addressed, at Department of Clinical Immunology and Biological Therapy, Box 41, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston TX 77030.

Received 2/15/88. Revised 4/27/88. Accepted 5/ 3/88.