title: Antitherapeutic antibody-mediated hepatotoxicity of recombinant human Apo2L/TRAIL in the cynomolgus monkey.
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.
authors: Safety Assessment, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Christina L
authors: CL
authors: Zuch de Zafra
authors: Department of Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Avi
authors: A
authors: Ashkenazi
authors: Oncology Biomarker Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Walter C
authors: WC
authors: Darbonne
authors: BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Melissa
authors: M
authors: Cheu
authors: Department of Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Klara
authors: K
authors: Totpal
authors: Safety Assessment, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Shirley
authors: S
authors: Ortega
authors: Late Stage Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Heather
authors: H
authors: Flores
authors: Charles River Laboratories Inc. (formerly Sierra Biomedical), 587 Dunn Circle, Sparks, NV 89431, USA.
authors: Mark D
authors: MD
authors: Walker
authors: Early Stage Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Bruce
authors: B
authors: Kabakoff
authors: Clinical Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Bert L
authors: BL
authors: Lum
authors: Toxicology Department, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
authors: Barbara J
authors: BJ
authors: Mounho-Zamora
authors: Department of Cancer Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Scot A
authors: SA
authors: Marsters
authors: Safety Assessment, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Noël O
authors: NO
authors: Dybdal
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use* / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D019169:Jurkat Cells; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D011994:Recombinant Proteins / Q000627:therapeutic use* / Q000633:toxicity*; D013045:Species Specificity; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use* / Q000633:toxicity*
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand