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Preparation of -Emitting ²¹³Bi-Labeled Antibody Constructs for Clinical Use

Memorial Sloan-Kettering Cancer Center, New York, New York

Correspondence: For correspondence or reprints contact: David A. Scheinberg, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.

ABSTRACT

Preclinical eavaluation of particle-emitting ²¹³Bi-labeled antibody constructs have demonstrated the specificity and potency of these agents in a variety of cancer systems. The transition of a ²¹³Bi-radiolabeled antibody from a preclinical construct to a clinical drug represented a difficult task that involved development of reliable and validated methodsto provide multiple MBq quantities of a pure, immunoreactive agent that met pharmaceutical standards to treat patients. Methods: The methods used for the preparation of (²¹³Bi)CHX-A-diethylenetriamine pentaacetic acid (DTPA)-HuM195, an 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, radio protection 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-HuM195 with ²¹³Bi 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 (²¹³Bi)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 ²²⁵Ac radionuclidic impurity was present at a level of 0.04 ± 0.03 x 10^-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 ²¹³Bi-labeled antibody constructs can be prepared and administered safely to humans at a wide range of therapeutic levels.

Key Words: particles • ²¹³Bi • HuM195 • monoclonal antibodies • therapy

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