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Critical Care

, 15:P262 | Cite as

Preclinical pharmacodynamics and safety profiling of AZD9773: a novel anti-TNFα polyclonal immune ovine Fab similar to D-CytoFab

  • P Newham
  • J Yates
  • S Das
  • J Kemp
  • J Young
  • P Ceuppens
  • F Brennan
  • R Knight
  • J Growcott
Poster presentation

Keywords

Surface Plasmon Resonance Cynomolgus Monkey Lyophilised Powder Principal Mediator Monitoring Electrocardiogram 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Introduction

The critical pathophysiological trigger of sepsis is thought to be a disturbance in the equilibrium between the proinflammatory response and concomitant anti-inflammatory mechanisms. Data show that the proinflammatory cytokine TNFα is a principal mediator of sepsis [1, 2]. AZD9773 is a sterile lyophilised powder for solution for i.v. infusion containing ovine immune fragments (Fabs) of IgG that bind to human TNFα. We explored the PD and safety profile of AZD9773 in cynomolgus monkeys. AZD9773 PD data are compared with D-CytoFab (a similar ovine anti-TNFα IgG immune Fab product) that showed clinical benefit in a phase IIb study [3].

Methods

AZD9773 binding and neutralisation of primate TNFα were assessed using surface plasmon resonance and TNFα-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 TNFα-mediated effects was determined by the inhibition of endotoxin-induced TNFα 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.

Results

There was no significant difference between AZD9773 and D-CytoFab in the binding of primate TNFα in vitro, and AZD9773 and D-CytoFab neutralised recombinant primate TNFα with only a twofold and 1.8-fold reduction in potency, respectively, compared with recombinant human TNFα. 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 TNFα 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.

Conclusions

Preclinical data indicate that AZD9773 has a good safety profile and is a well-tolerated anti-TNFα immune Fab product with PD characteristics similar to D-CytoFab.

References

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    Crit Care Clin. 1989, 5: 1.Google Scholar
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    Crit Care Med. 1989, 17: 389. 10.1097/00003246-198905000-00002Google Scholar
  3. 3.
    Crit Care Med. 2006, 34: 2271. 10.1097/01.CCM.0000230385.82679.34Google Scholar

Copyright information

© Newham et al. 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • P Newham
    • 1
  • J Yates
    • 1
  • S Das
    • 1
  • J Kemp
    • 1
  • J Young
    • 1
  • P Ceuppens
    • 1
  • F Brennan
    • 2
  • R Knight
    • 1
  • J Growcott
    • 1
  1. 1.AstraZenecaMacclesfieldUK
  2. 2.NovartisBaselSwitzerland

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