Imaging, biodistribution, and toxicology evaluation of 212Pb-TCMC-trastuzumab in nonhuman primates

IntroductionThe biodistribution and toxicology of a radiotherapeutic 212Pb-trastuzumab conjugate were evaluated in nonhuman primates to meet the investigational new drug requirements prior to a phase I clinical trial in human subjects.MethodsMale cynomolgus monkeys (n = 3/group) were injected intraperitoneally with the 212Pb-trastuzumab conjugate and terminated at 8 h, 10 d, and 90 d 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 48 h following injection. Biodistribution analyses were conducted at 8 h; all tissues and time points were evaluated for macroscopic and microscopic pathology. Blood samples were taken throughout the 90 d study period for assessment of hematology parameters and serum chemistry parameters.ResultsQuantitative gamma camera imaging and region-of-interest analyses of phantoms and monkeys indicated that 95.5 ± 5.0% of the decay-corrected 212Pb activity was retained in the peritoneal region up to 48 h following administration of the 212Pb-trastuzumab. Gamma-ray spectroscopy analyses confirmed that 87.6 ± 4.5% of the decay-corrected 212Bi 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.ConclusionIn vivo imaging and biodistribution analyses showed that about 90% of both 212Pb and decay product 212Bi 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 212Pb-trastuzumab conjugate supports its clinical assessment in humans.