Preclinical pharmacodynamics and safety profiling of AZD9773: A novel anti-TNF-α polyclonal immune ovine Fab similar to D-CytoFab

The critical pathophysiological trigger of sepsis is thought to be a disturbance in the equilibrium between the pro-inflammatory response and concomitant anti-inflammatory mechanisms. Data show that the pro-inflammatory cytokine, TNF-α, is a principal mediator of sepsis. AZD9773 is a sterile lyophilised powder for solution for IV infusion containing ovine immune fragments (Fabs) of IgG that bind to human TNF-α. We explored the pharmacodynamics (PD) and safety profile of AZD9773 in cynomolgus monkeys. AZD9773 PD data are compared to “D-CytoFab” (a similar ovine anti-TNF-α IgG immune Fab product) that showed clinical benefit in a phase IIb study (Rice et al 2006).

Methods: AZD9773 binding and neutralisation of primate TNF-α were assessed using surface plasmon resonance and TNF-α-mediated cytotoxicity assay using L929 cells, respectively. AZD9773 did not show any unexpected binding to frozen primate tissue. The in vivo ability of either AZD9773 or D-CytoFab to suppress TNF-α-mediated effects was determined by the inhibition of endotoxin-induced TNF-α and IL-6 production in cynomolgus monkeys. A mathematical (PK-PD) model was constructed to describe the cytokine PD profile. Safety assessments included monitoring electrocardiogram outputs, heart rate, blood pressure and toxicology indices in cynomolgus monkeys administered with AZD9773.

There was no significant difference between AZD9773 and D-CytoFab in the binding of primate TNF-α in vitro and, AZD9773 and D-CytoFab neutralised recombinant primate TNF-α with only a 2-fold and 1.8-fold reduction in potency, respectively, compared to recombinant human TNF-α. Both AZD9773 and D-CytoFab at equivalent doses with comparable exposure significantly suppressed endotoxin-induced IL-6 production in cynomolgus monkeys to a similar extent. PK-PD analysis revealed the effect of AZD9773 and D-CytoFab on serum TNF-α and IL-6 levels and estimated model parameters were not significantly different. No toxicologically significant findings were observed in cynomolgus monkeys with AZD9773 at doses significantly higher than those currently under clinical investigation.
Preclinical data indicate that AZD9773 has a good safety profile and is a well tolerated anti-TNF-α immune Fab product with PD characteristics similar to D-CytoFab.

All authors are current or former employees of AstraZeneca.