Walter & Eliza Hall Institute of Medical Research
Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a humanized mouse model
Jamie L Brady1,2, Leonard C Harrison1,2, David J Goodman4, Peter J Cowan3,5, Wayne J Hawthorne6, Philip J O'Connell6, Robyn M Sutherland1,2, Andrew M Lew1,2,7.
1Department of Medical Biology, The University of Melbourne, Parkville, Australia; 2Walter & Eliza Hall Insitiute of Medical Research, Parkville, Australia; 3Department of Medicine, The University of Melbourne, Parkville, Australia; 4Department of Nephrology, St Vincent's Hospital, Fitzroy, Australia; 5Immunology Research Centre, St Vincent's Hospital, Fitzroy, Australia; 6Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, Australia; 7Department of Microbiology and Immunology, The University of Melbourne, Parkville, Australia
Monoclonal antibodies (mAb) have been a spectacular clinical and commercial success in the treatment of cancer and autoimmune diseases. Many of these mAb (e.g. OKT3, Campath-1H, rituximab, infliximab) are against surface or secreted products of lymphocytes. However, mAb can have a variety of adverse effects including fever, chills and nausea. This is probably a result of cytokine release, which is most seriously manifest as a ‘cytokine storm’ as highlighted by the TGN1412 (anti-CD28) trial. Prediction of adverse effects of mAb would be clinically advantageous and numerous in vitro assays attempting to predict adverse effects have been reported.
We have used an in vivo humanized mouse model (huSCID) to detect adverse effects in response to OKT3, Campath-1H or the polyclonal antibody preparation anti-thymocyte globulin. We assessed clinical signs (appearance, behavior, body temperature) and performed laboratory testing to quantify plasma cytokines and lymphocyte activation markers immediately ex vivo. We performed dose titration and used two routes of administration viz. intraperitoneal (IP) and intravenous (IV) to reflect slow and rapid infusion respectively. We found that the administration of each of the antibodies to huSCID 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 pre-clinical testing, as a more representative and robust means of assessing potential adverse effects of mAb prior to their human use.
Victorian State Government Operational Infrastructure Support. Australian Government NH&MRC IRIIS. Juvenile Diabetes Research Foundation. Australian National Health and Medical Research Council. Rebecca L. Cooper Foundation.
 Clinical & Translational Immunology (2014) 3, e29; doi:10.1038/cti.2014.28
11:00 - 12:30
|Islet Xenotransplantation||Anti-CD2 producing pig xenografts effect localized depletion of human T cells in a humanized mouse model||Room 109|
15:30 - 17:00
|Immunology||Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a humanized mouse model||Room 111-112|