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Brady JL, Harrison LC, Goodman DJ, et al. Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model. Clin Transl Immunology. 2014;3(12):e29doi: 10.1038/cti.2014.28.
Brady, J. L., Harrison, L. C., Goodman, D. J., Cowan, P. J., Hawthorne, W. J., O'Connell, P. J., Sutherland, R. M., & Lew, A. M. (2014). Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model. Clinical & translational immunology, 3(12), e29. https://doi.org/10.1038/cti.2014.28
Brady, Jamie L, et al. "Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model." Clinical & translational immunology vol. 3,12 (2014): e29. doi: https://doi.org/10.1038/cti.2014.28
Brady JL, Harrison LC, Goodman DJ, Cowan PJ, Hawthorne WJ, O'Connell PJ, Sutherland RM, Lew AM. Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model. Clin Transl Immunology. 2014 Dec 19;3(12):e29. doi: 10.1038/cti.2014.28. eCollection 2014 Dec. PMID: 25587392; PMCID: PMC4282178.
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Clin Transl Immunology. 2014 Dec 19;3(12):e29. doi: 10.1038/cti.2014.28. eCollection 2014 Dec.

Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu-SCID model.

Clinical & translational immunology

Jamie L Brady, Leonard C Harrison, David J Goodman, Peter J Cowan, Wayne J Hawthorne, Philip J O'Connell, Robyn M Sutherland, Andrew M Lew

Affiliations

  1. Walter and Eliza Hall Institute of Medical Research , Parkville, Victoria, Australia ; Department of Medical Biology, The University of Melbourne , Parkville, Victoria, Australia.
  2. Department of Nephrology, St Vincent's Hospital , Fitzroy, Victoria, Australia.
  3. Immunology Research Centre, St Vincent's Hospital , Fitzroy, Victoria, Australia ; Department of Medicine, The University of Melbourne , Parkville, Victoria, Australia.
  4. Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital , Westmead, New South Wales, Australia.

PMID: 25587392 PMCID: PMC4282178 DOI: 10.1038/cti.2014.28

Abstract

Monoclonal antibodies (mAbs) have been a spectacular clinical and commercial success in the treatment of cancer and autoimmune diseases. Many of these mAbs (for example, OKT3, Campath-1H, rituximab and infliximab) are against surface or secreted products of lymphocytes. However, mAbs can have a variety of adverse effects including fever, chills and nausea. This is probably a result of cytokine release, which is most seriously manifested as a 'cytokine storm' as highlighted by the TGN1412 (anti-CD28) trial. Prediction of adverse effects of mAbs would be clinically advantageous and numerous in vitro assays attempting to predict adverse effects have been reported. Here, we report an in vivo humanized mouse model to detect adverse effects in response to OKT3, Campath-1H or the polyclonal Ab preparation anti-thymocyte globulin. We found that the administration of each of these Abs to humanized mice led to acute clinical symptoms such as piloerection, hypomotility and hypothermia, particularly when delivered via the intravenous route. A cytokine storm occurred in the humanized mice receiving OKT3. This model system is a potentially useful tool to predict adverse effects and select initial doses for first-in-human trials. We would advocate this in vivo model, in addition to current in vitro preclinical testing, as a more representative and robust means of assessing potential adverse effects of mAb before their human use.

References

  1. Adv Immunol. 1992;51:1-84 - PubMed
  2. Ther Immunol. 1995 Aug;2(4):183-90 - PubMed
  3. PLoS One. 2013 Aug 05;8(8):e71057 - PubMed
  4. Sci Transl Med. 2012 Jan 25;4(118):118ra12 - PubMed
  5. Nat Rev Immunol. 2012 Nov;12(11):786-98 - PubMed
  6. Mol Pharm. 2013 Apr 1;10(4):1425-31 - PubMed
  7. Xenotransplantation. 2013 Mar-Apr;20(2):100-9 - PubMed
  8. Transplantation. 1990 Apr;49(4):697-702 - PubMed
  9. FASEB J. 2008 Mar;22(3):659-61 - PubMed
  10. Blood. 2005 Sep 1;106(5):1565-73 - PubMed
  11. Am J Transplant. 2012 Oct;12(10):2630-40 - PubMed
  12. Nat Rev Immunol. 2012 Oct;12(10):740; author reply 740 - PubMed
  13. Adv Immunol. 2004;82:155-215 - PubMed
  14. Br J Pharmacol. 2010 Oct;161(3):512-26 - PubMed
  15. Transplantation. 1989 Apr;47(4):606-8 - PubMed
  16. Expert Rev Clin Immunol. 2009 Sep;5(5):499-521 - PubMed
  17. Pharmacotherapy. 2006 Dec;26(12 ):1771-83 - PubMed
  18. Int Immunopharmacol. 2011 Nov;11(11):1697-705 - PubMed
  19. Brain. 1996 Feb;119 ( Pt 1):225-37 - PubMed
  20. Med Oncol. 2001;18(2):99-107 - PubMed
  21. J Immunol Methods. 2010 Jan 31;352(1-2):1-12 - PubMed
  22. J Immunol. 1991 Feb 15;146(4):1184-91 - PubMed
  23. Oncoimmunology. 2013 Oct 1;2(10):e26333 - PubMed
  24. Nat Rev Drug Discov. 2010 Apr;9(4):325-38 - PubMed
  25. Science. 2013 Dec 20;342(6165):1432-3 - PubMed
  26. Drugs. 1996 May;51(5):865-94 - PubMed
  27. J Immunol. 2007 Sep 1;179(5):3325-31 - PubMed
  28. J Immunol. 2014 Jul 15;193(2):587-96 - PubMed
  29. Lancet. 2006 Nov 4;368(9547):1569-70; author reply 1570 - PubMed
  30. Br J Clin Pharmacol. 2013 Aug;76(2):299-315 - PubMed

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