Toxicological Studies of 212Pb Intravenously or Intraperitoneally Injected into Mice for a Phase 1 Trial.

Diane Milenic,María Solivella,Kwamena Baidoo,Eileen Banaga,Sarah Besnainou,Alfredo Molinolo,Martin Brechbiel,Julien Torgue

doi:10.3390/ph8030416

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.

Highlights

The radionuclide, 212Pb, has been a focus of investigation for radioimmuno-therapy (RIT) [1,2,3,4,5,6,7,8,9,10,11,12,13] as well as a supply of cytotoxic α-particles from the decay of its 212Bi daughter, and the strategy of using the 212Pb as an in vivo generator for 212Bi circumvents the logistical difficulties of working directly with the short-lived 212Bi (T1⁄2 60.6 min)
In those mice that received the 212Pb by i.p. injection, deaths occurred in the 0.555 MBq, 1.11 MBq, 1.488 MBq and 1.85 MBq
To expedite the study and due to the logistics of conducting the study, mice in the 90 days groups were injected with the 212Pb first, the 7 days groups were injected at later times

Summary

Introduction

The radionuclide, 212Pb, has been a focus of investigation for radioimmuno-therapy (RIT) [1,2,3,4,5,6,7,8,9,10,11,12,13] as well as a supply of cytotoxic α-particles from the decay of its 212Bi daughter, and the strategy of using the 212Pb as an in vivo generator for 212Bi circumvents the logistical difficulties of working directly with the short-lived 212Bi (T1⁄2 60.6 min). In 2011, a phase I clinical trial (NCT01384253), sponsored by AREVA Med LLC (Bethesda, MD, USA), was initiated at the UAB to determine the toxicity profile of 212Pb-TCMC-trastuzumab, its dose-limiting toxicities, and its anti-tumor effects in patients. Tumors were required to have either a score of at least 1+ by immunohistochemistry in more than 10% of the cells or have demonstrated HER-2 amplification by fluorescent in situ hybridization, or the patient’s HER-2 serum levels had to be greater than 15ng/mL by ELISA. This was the first such human study of 212Pb-radioimmunotherapy

Objectives

Results

Conclusion