Antitherapeutic antibody-mediated hepatotoxicity of recombinant human Apo2L/TRAIL in the cynomolgus monkey
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Updated: Jul 31, 2026
Radial Mobility and Cytotoxic Function of Retroviral Replicating Vector Transduced, Non-adherent Alloresponsive T Lymphocytes
Published on: February 11, 2015
Christina L Zuch de Zafra1, Avi Ashkenazi2, Walter C Darbonne3
1Safety Assessment, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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.
Insights
Recombinant human Apo2L/TRAIL, a cancer therapeutic, caused liver toxicity in monkeys due to antibodies. Identifying specific amino acids responsible for this immune response allowed safe human trials.
Area of Science:
- Immunology
- Toxicology
- Biochemistry
Background:
- Apo2L/TRAIL is a tumor necrosis factor superfamily member and apoptosis inducer, investigated as a cancer therapeutic.
- Recombinant human Apo2L/TRAIL (rhuApo2L/TRAIL) showed promise, but nonclinical safety studies were required.
- Cynomolgus monkeys were selected for safety assessment due to high protein homology and receptor expression.
Purpose of the Study:
- To evaluate the safety of rhuApo2L/TRAIL in nonclinical toxicology studies.
- To investigate the mechanism of hepatotoxicity observed in cynomolgus monkeys treated with rhuApo2L/TRAIL.
- To elucidate the role of antitherapeutic antibodies (ATAs) in rhuApo2L/TRAIL-induced hepatotoxicity.
Main Methods:
- Repeat-dose toxicology studies in cynomolgus monkeys.
- Analysis of antibody development and characterization (ATAs).
- In vivo studies comparing human and cynomolgus Apo2L/TRAIL efficacy and immunogenicity.
Main Results:
- Hepatotoxicity was observed in monkeys receiving rhuApo2L/TRAIL, correlating with ATA development.
- Cynomolgus ATAs augmented rhuApo2L/TRAIL cytotoxicity but not the endogenous cynomolgus protein.
- Differences in four amino acids, three surface-exposed, between human and cynomolgus Apo2L/TRAIL were identified as epitopes for cross-species ATAs.
Conclusions:
- A hapten-independent mechanism of immune-mediated hepatotoxicity was identified, involving cross-species ATAs triggered by specific amino acid differences.
- These ATAs crosslinked rhuApo2L/TRAIL, leading to hepatocyte apoptosis.
- Understanding this mechanism facilitated the successful progression of rhuApo2L/TRAIL into human clinical trials.
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