title: Imaging, biodistribution, and toxicology evaluation of (212)Pb-TCMC-trastuzumab in nonhuman primates.
abstract: The biodistribution and toxicology of a radiotherapeutic (212)Pb-trastuzumab conjugate were evaluated in nonhuman primates to meet the investigational new drug requirements prior to a phase I clinical trial in human subjects.
  
  
  
  Male cynomolgus monkeys (n=3/group) were injected intraperitoneally with the (212)Pb-trastuzumab conjugate and terminated at 8h, 10d, and 90d post-injection. Quantitative imaging studies in phantoms and monkeys were conducted using a planar gamma camera and a high purity germanium (HPGe) detector out to 48h following injection. Biodistribution analyses were conducted at 8h; all tissues and time points were evaluated for macroscopic and microscopic pathology. Blood samples were taken throughout the 90d study period for assessment of hematology parameters and serum chemistry parameters.
  
  
  
  Quantitative gamma camera imaging and region-of-interest analyses of phantoms and monkeys indicated that 95.5±5.0% of the decay-corrected (212)Pb activity was retained in the peritoneal region up to 48h following administration of the (212)Pb-trastuzumab. Gamma-ray spectroscopy analyses confirmed that 87.6±4.5% of the decay-corrected (212)Bi activity was also retained in the peritoneal cavity during this time. Serum chemistry parameters for all groups always fell within normal ranges. Gross and histopathology evaluations showed no radiation-related toxicity in any tissue at any time.
  
  
  
  In vivo imaging and biodistribution analyses showed that about 90% of both (212)Pb and decay product (212)Bi remained in the monkey peritoneal cavity. The imaging methods could also be applied to human subjects. The lack of toxicity observed in monkeys following intraperitoneal injection of the (212)Pb-trastuzumab conjugate supports its clinical assessment in humans.
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Kasten
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Azure
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.affiliation: Dade Moeller Health Group, Richland, WA, USA.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.affiliation: Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: kurtzinn@uab.edu.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Zinn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D007856:Lead Radioisotopes; D008252:Macaca fascicularis; D008297:Male; D011877:Radionuclide Imaging / Q000295:instrumentation / Q000379:methods*; D014018:Tissue Distribution; D018675:Toxicity Tests; D000068878:Trastuzumab / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D007856:Lead Radioisotopes; D000068878:Trastuzumab
keywords: (212)Pb; Biodistribution; Imaging; Nonhuman primate; Trastuzumab