title: Toxicological Studies of 212Pb Intravenously or Intraperitoneally Injected into Mice for a Phase 1 Trial.
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.
authors.affiliation: Radioimmune & 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.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. amolinol@mail.nih.gov.
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. solivellams@yahoo.com.
authors.forename: María S
authors.initials: MS
authors.lastname: Solivella
authors.affiliation: Areva Med LLC, 4800 Hampden Lane, Suite 200, Bethesda, MD 20817, USA. Eileen.banaga@areva.com.
authors.forename: Eileen
authors.initials: E
authors.lastname: Banaga
authors.affiliation: Areva Med LLC, 4800 Hampden Lane, Suite 200, Bethesda, MD 20817, USA. Julien.torgue@areva.com.
authors.forename: Julien
authors.initials: J
authors.lastname: Torgue
authors.affiliation: Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. sarah.besnainou@gmail.com.
authors.forename: Sarah
authors.initials: S
authors.lastname: Besnainou
authors.affiliation: Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. martinwb@mail.nih.gov.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
authors.affiliation: Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. baidook@mail.nih.gov.
authors.forename: Kwamena E
authors.initials: KE
authors.lastname: Baidoo
keywords: FDA toxicity study; Pb-212; radioimmunotherapy; targeted alpha-radiation