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Preclinical evaluation of a particle-emitting ^sup 213^Bi-labeled antibody constructs have demonstrated the specificity and potency of these agents in a variety of cancer systems. The transition of a ^sup 213^Bi-radiolabeled antibody from a preclinical construct to a clinical drug represented a difficult task that involved development of reliable and validated methods to provide multiple MBq quantities of a pure, immunoreactive agent that met pharmaceutical standards to treat patients. Methods: The methods used for the preparation of (^sup 213^Bi)CHX-A-diethylenetriamine pentaacetic acid (DTPA)-HuM 195, an alpha particle-emitting anti-CD33 antibody construct for therapy of myeloid leukemias, is used as a specific example. This article describes methods for reagent purification, drug labeling, radioprotection and chromatographic purification. Quality of the drug is evaluated using radiochemical incorporation and purity assays with instant thin-layer chromatography (ITLC) and high-performance liquid chromatography (HPLC), determination of cell-based antibody total immunoreactivity, small animal safety, pyrogen level, sterility and radionuclidic purity. Results: Sixty-seven doses were prepared. Individual doses ranged from 148 to 814 MBq. Specific activities ranged from 329 to 766 MBq/mg. The radiolabeling efficiency (median +/- SD) of CHX-A-DTPA-HuMl 95 with ^sup 213^Bi was 81% +/- 9% (n = 67) after 9 min. The construct was purified by size-exclusion chromatography and was found to be 99% +/- 2% pure (n = 67) by either ITLC or HPLC methods. The immunoreactivity of (^sup 213^Bi)CHX-A-DTPA-- HuM195 was 89% +/- 9% (n = 44) and was independent of the specific activity. The formulated pharmaceutical was found to contain <=4 +/- 1 EU/mL pyrogens (n = 66); all samples examined were sterile. An ^sup 225^Ac radionuclidic impurity was present at a level of 0.04 +/- 0.03 x 10^sup -6^/mL (n = 10) in a product volume of 7.4 +/-- 0.5 mL (n = 67). Each of the 67 doses was injected intravenously into patients without complication as part of a phase I clinical trial. Conclusion: These data show that ^sup 213^Bi-labeled antibody constructs can be prepared and administered safely to humans at a wide range of therapeutic levels.
Key Words: alpha particles; ^sup 213^Bi; HuM195; monoclonal antibodies; therapy
J Nucl Med 1999; 40:1722-1727
Bismuth-213 is an alpha particle-emitting radionuclide that has been demonstrated in several preclinical investigations (1-10) to be an extremely potent cytotoxic agent and specific when attached...