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

详细信息    查看全文

• 作者：Benjamin B. Kasten^a ; Michael T. Azure^a ; Trenton R. Schoeb^b ; Darrell R. Fisher^c ; Kurt R. Zinn^a ; ^{kurtzinn@uab.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：212Pb ; Trastuzumab ; Nonhuman primate ; Biodistribution ; Imaging
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：43
• 期：7
• 页码：391-396
• 全文大小：605 K

文摘

The 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.

Methods

Male 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.

Results

Quantitative 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.

Conclusion

In 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.