Table 1. Correlation of anti-rhuApo2L/TRAIL antibodies and hepatotoxicity in cynomolgus monkey toxicology studies.
| Study | rhuApo2L/TRAIL dose level (mg/kg) | No/Group | No. with ATA titer – ELISA | No. with ATA titer – RIP | No. with crosslinking activitya | No. with ALT increaseb | No. with liver histopathology | No. of treatment-related deathsc |
|---|---|---|---|---|---|---|---|---|
| 4-week repeat-dose study | 0 | 12 | 0 | NT | NT | 0 | 0 | 0 |
| 10 | 8 | 0 | NT | NT | 0 | 0 | 0 | |
| 30 | 8 | 0 | NT | NT | 0 | 0 | 0 | |
| 100d | 12 | 0 | NT | NT | 1 | 1 | 0 | |
| 100e | 12 | 0 | NT | NT | 0 | 0 | 0 | |
| Concomitant renal injury model | 0 | 4 | 0 | NT | NT | 0 | 0 | 0 |
| 30 | 4 | 0 | NT | NT | 1 | 2 | 0 | |
| 100 | 4 | 0 | NT | NT | 2 | 1 | 1 | |
| 100f | 12 | 3 | 7 | 6 | 11 | 2 | 2 | |
| Sequential renal injury model | 0 | 9 | 0 | 0 | 0 | 0 | 0 | 0 |
| 10 | 8 | 1 | 1 | 1 | 1 | 0 | 0 | |
| 30 | 8 | 1 | 6 | 2 | 2 | 2 | 2 | |
| 100 | 12 | 5 | 10 | 5 | 4 | 3 | 1g |
Abbreviation: NT, not tested.
a
Crosslinking activity determined by Jurkat cytotoxicity assay.
b
Increase in ALT greater than twice the upper limit of the normal range.
c
Deaths related to rhuApo2L/TRAIL hepatotoxicity.
d
Daily administration for 28 days.
e
Two cycles of treatment (5d q3wk) over 28 days.
f
Concomitant cisplatin+100 mg/kg rhuApo2L/TRAIL group from second renal injury model study.
g
Animal died of a study procedure-related hemorrhage; severe hepatocellular necrosis was observed microscopically but was not the cause of death per se.