| Abstract: |
Preclinical evaluation of α 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 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 (213Bi)CHX-A-diethylenetriamine pentaacetic acid (DTPA)- HuM195, an α 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-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. |
| Keywords: |
antineoplastic agents; radiation dose; quality control; algorithms; monoclonal antibodies; antibodies, monoclonal; isotope labeling; leukemia, myeloid; pyrogen; high performance liquid chromatography; antigens, cd; radioisotopes; drug determination; therapy; thin layer chromatography; antigens, differentiation, myelomonocytic; hum195; alpha radiation; bismuth; alpha particles; actinium; monoclonal antibody m 195; α particles; clinical trials, phase i; pentetic acid derivative; humans; priority journal; article; gel permeation chromatography; 213bi
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