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Preparation of alpha-emitting 213Bi-labeled antibody constructs for clinical use
1Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Unlabelled:
Preclinical evaluation of alpha 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 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 immunereactivity, 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 < or =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.
Insights
Alpha particle-emitting bismuth-213 (213Bi)-labeled antibody constructs are potent cancer therapies. This study details the successful preparation and administration of these agents, demonstrating their safety and efficacy in patients.
Area of Science:
- Radiopharmaceutical therapy
- Oncology
- Antibody-drug conjugates
Background:
- Preclinical studies show alpha-emitting 213Bi-labeled antibodies are potent and specific cancer therapies.
- Transitioning these agents from preclinical to clinical use requires validated methods for producing pharmaceutical-grade quantities.
Purpose of the Study:
- To describe the methods for preparing and quality controlling 213Bi-labeled antibody constructs for clinical use.
- To evaluate the safety and efficacy of these agents in a Phase I clinical trial.
Main Methods:
- Preparation of (213Bi)CHX-A-diethylenetriamine pentaacetic acid (DTPA)-HuM195, an anti-CD33 antibody construct.
- Reagent purification, drug labeling, radioprotection, and chromatographic purification.
- Quality control assays including radiochemical purity, immunoreactivity, pyrogen levels, and sterility.
Main Results:
- Sixty-seven doses ranging from 148 to 814 MBq were prepared with high radiolabeling efficiency (81%) and purity (99%).
- The antibody construct maintained high immunoreactivity (89%) and was found to be sterile and pyrogen-free.
- All 67 doses were safely administered intravenously to patients in a Phase I clinical trial.
Conclusions:
- Validated methods enable the production of pharmaceutical-grade 213Bi-labeled antibody constructs.
- These agents can be safely administered to humans at therapeutic levels, supporting their clinical application in cancer treatment.