Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a hu‐SCID model. Issue 12 (19th December 2014)

• Record Type: Journal Article
• Authors: Brady, Jamie L; Harrison, Leonard C; Goodman, David J; Cowan, Peter J; Hawthorne, Wayne J; O'Connell, Philip J; Sutherland, Robyn M; Lew, Andrew M
• Is Part Of: Clinical & translational immunology. Volume 3:Issue 12 (2014)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2014-12-19
• Subjects: Immunologic diseases -- Periodicals; Immunology -- Periodicals; Clinical medicine -- Periodicals; Immune System Diseases -- therapy; Immunotherapy; Immunologic Factors -- therapeutic use; Translational Medical Research; Molecular Targeted Therapy; Clinical medicine; Immunologic diseases; Immunology; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.079
• DOI: 10.1038/cti.2014.28
• Languages: English
• ISSNs: 2050-0068

Abstract

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. Antibody therapy: Animal testing with a human touch: Researchers in Australia have used mice with 'humanized' immune systems to detect side effects from therapeutic antibodies. The target recognition capabilities that make antibodies a critical component of the immune system also make them valuable therapeutic agents for inhibiting disease‐related proteins. However, antibody drugs can also trigger adverse immune reactions, and animal models may be a poor predictor of such toxicity. In pursuit of a better model, Andrew Lew of the Walter and Eliza Hall Institute of Medical Research and colleagues transplanted human immune cells into immunodeficient mice. They tested three antibodies‐all in clinical use‐using various doses and routes of delivery, and identified distinct differences in the associated levels of toxicity. Based on these data, Lew and colleagues conclude that their model could help plan safer dosing strategies for future clinical trials.