Abstract
Apo2L/TRAIL is a member of the tumor necrosis factor superfamily and an important inducer of apoptosis. Recombinant human (rhu) Apo2L/TRAIL has been attractive as a potential cancer therapeutic because many types of tumor cells are sensitive to its apoptosis-inducing effects. Nonclinical toxicology studies were conducted to evaluate the safety of rhuApo2L/TRAIL for possible use in humans. The cynomolgus monkey was chosen for this safety assessment based on high protein sequence homology between human and cynomolgus Apo2L/TRAIL and comparable expression of their receptors. Although hepatotoxicity was observed in repeat-dose monkey studies with rhuApo2L/TRAIL, all animals that displayed hepatotoxicity had developed antitherapeutic antibodies (ATAs). The cynomolgus ATAs augmented the cytotoxicity of rhuApo2L/TRAIL but not of its cynomolgus counterpart. Of note, human and cynomolgus Apo2L/TRAIL differ by four amino acids, three of which are surface-exposed. In vivo studies comparing human and cynomolgus Apo2L/TRAIL supported the conclusion that these distinct amino acids served as epitopes for cross-species ATAs, capable of crosslinking rhuApo2L/TRAIL and thus triggering hepatocyte apoptosis. We describe a hapten-independent mechanism of immune-mediated, drug-related hepatotoxicity – in this case – associated with the administration of a human recombinant protein in monkeys. The elucidation of this mechanism enabled successful transition of rhuApo2L/TRAIL into human clinical trials.
Highlights
Ligand superfamily, is critically involved in the process of apoptosis.[1,2] Apo2L/TRAIL is a type II transmembrane protein with an extracellular portion that can bind to death receptors
The sensitivity of tumor cells to Apo2L/TRAIL makes it attractive as a potential anticancer therapeutic, but drug development efforts have been hampered by literature reports of hepatotoxicity of nonoptimized versions of Apo2L/TRAIL23 and by observations of hepatotoxicity as described in this report, as well as by an apparent lack of clinical efficacy.[18]
The rhuApo2L/TRAIL clinical development plan included the possible treatment of patients with nephrotoxic chemotherapy agents
Summary
Ligand superfamily, is critically involved in the process of apoptosis.[1,2] Apo2L/TRAIL is a type II transmembrane protein with an extracellular portion that can bind to death receptors. Clinical studies to date have not shown broad efficacy of Apo2L/ TRAIL-related agents,[18] generating interest in the development of more potent agonists targeting this pathway.[19,20,21]. Understanding the safety profile of agents that target the Apo2L/TRAIL receptors is critical for the development of second-generation molecules that may prove to be more efficacious.
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