Related Experiment Videos
Toxicological Studies of 212Pb Intravenously or Intraperitoneally Injected into Mice for a Phase 1 Trial
Diane E Milenic1, Alfredo A Molinolo2, María S Solivella3
1Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. milenicd@mail.nih.gov.
Abstract:
Faced with the novelty of a 212Pb-labeled monoclonal antibody (mAb) for clinical translation, concerns were expressed by the Food and Drug Administration (FDA) regarding 212Pb prematurely released from the mAb-chelate conjugate. The objective of this study was to simulate the worst case scenario of such a failure. Groups of Balb/c mice (n = 9-20) were administered 212Pb by intraperitoneal (0.0925-1.85 MBq) or intravenous (0.0925-1.11 MBq) injection and then euthanized at 7 or 90 days to assess acute or chronic effects. Weights were recorded prior to injection of the 212Pb and at the end of the observation periods. Blood samples were collected for clinical chemistry and blood cell analysis. Thirty tissues were harvested and formalin fixed for histopathological examination. Treatment related effects of the 212Pb were observed in the bone marrow, spleen, kidneys and the liver. Histological alterations in these organs were considered mild to moderate, indicating low grade toxicity, and not considered severe enough to affect function. This data was presented to the FDA and determined to be acceptable. The clinical trial with 212Pb-TCMC-trastuzumab was approved in January 2011 and the trial opened at the University of Alabama at Birmingham (UAB) in July.
Insights
This study simulated the release of lead-212 (212Pb) from monoclonal antibody (mAb) conjugates. Mild toxicity was observed in mice, supporting the safety of 212Pb-labeled mAbs for clinical trials.
Area of Science:
- Radiopharmaceutical therapy
- Preclinical toxicology
- Monoclonal antibody conjugates
Background:
- Concerns exist regarding premature release of lead-212 (212Pb) from monoclonal antibody (mAb) conjugates intended for clinical use.
- Regulatory bodies like the Food and Drug Administration (FDA) require thorough safety assessments for novel radiolabeled therapeutics.
Purpose of the Study:
- To simulate a worst-case scenario of 212Pb premature release from a mAb-chelate conjugate.
- To evaluate the acute and chronic toxicity of 212Pb in a preclinical mouse model.
- To provide data supporting the clinical translation of 212Pb-labeled mAbs.
Main Methods:
- Balb/c mice received intraperitoneal or intravenous injections of 212Pb.
- Animals were euthanized at 7 or 90 days post-injection for toxicity assessment.
- Body weights, clinical chemistry, blood cell counts, and histopathology of 30 tissues were analyzed.
Main Results:
- Treatment-related effects of 212Pb were observed in bone marrow, spleen, kidneys, and liver.
- Histological alterations were mild to moderate, indicating low-grade toxicity.
- Observed toxicity was not severe enough to impair organ function.
Conclusions:
- The simulated premature release of 212Pb from mAb conjugates resulted in mild to moderate toxicity in mice.
- The preclinical safety data were deemed acceptable by the FDA.
- This study supported the approval and initiation of a clinical trial using 212Pb-TCMC-trastuzumab.
