Autoimmunity potential, evaluation

Alternative Approach for Evaluation of Autoimmunity Potential of Chemicals... 

STRATEGY FOR EVALUATION OF AUTOIMMUNITY POTENTIAL IN DRUG DEVELOPMENT... 

The evaluation of autoimmunity potential of drug candidates in animal studies would have value if the results could make an impact on the conduct of clinical trials during drug development, e.g., influence selecting patient population, clinical monitoring, dose selection and/or escalation, stopping criteria, or other safety decisions. 

A number of chimerized, humanized, and one human mAb have now been approved for therapeutic use in humans in the treatment of autoimmunity, malignancy, infection and cardiovascular disease (Table 1). Some of the currently licensed mAb will be discussed here. A much larger number of mAb are currently being evaluated in Phase I, II and III trials. In general, chimeric, humanized and human mAb are very well tolerated with few side effects. Chimeric or humanized mAb still have the potential to evoke host immune response to the variable domains or CDRs of the antibody so-called HACA (human anti-chimeric antibody) or HAHA (human anti-human antibody) responses, although these responses are uncommon. Short-lived and occasionally severe infusion-related acute hypersensitivity reactions such as fever, skin itching, shivering, respiratory compromise and low blood pressure sometimes occur-. Such effects may... 

Much of the methods development and validation efforts in the past have been focused on evaluation of immunosuppression and contact or dermal sensitization. Currently available animal models and assays are not valid to assess the potential for systemic hypersensitivity and, at this time, reliable models to assess autoimmunity are not available. 

Kimber I, Dearman RJ. Evaluation of respiratory sensitization potential of chemicals. In Ballantyne B, Marrs TC, Syversen T, eds. General and Applied Toxicology. Vol. 2. London Macmillan, 2000. Kretz-Rommel A, Rubin RL. Disruption of positive selection of thymocytes causes autoimmunity. Nat... 

Potential therapeutic benefits of antioxidants to reduce intracellular oxidative stress have not yet been evaluated in vasculific neuropathy associated w ith autoimmune disease. Such anti-oxidants as vitamin E, a-lipoic acid or benfotiamine may be effective in interrupting the pro-inflammatory transcription factors and subsequent NF-[kappa]B regulated cytokines that initiate and maintain inflammation associated w ith vasculific neuropathy (Haselbeck et al., 2004). 

Because of its multiple effects on immunoinflammatory response, recombinant IL-12 has been shown to have therapeutic activity in a variety of mouse tumor and infectious disease models and is being evaluated in clinical trials in human cancer patients. IL-12 also appears to play a role in the genesis of some forms of immunopathology, including endotoxin-induced shock and some autoimmune diseases associated with aberrant Thl activity. Therefore IL-12 antagonists may also have therapeutic potential in the treatment of autoimmune disorders. In addition, intraocular injection of IL-12 significantly inhibited the development of endotoxin-induced intraocular inflammation, suggesting that IL-... 

ICH S8 includes unintended immune enhancement as an adverse effect, which should be considered in evaluating the potential immunotoxicity of drugs. Specifically excluded are drug-specific allergenicity and autoimmunity. This is perhaps a confusing exemption and should be discussed. 

When a new drug candidate has characteristics indicating a possible reactivity with the immune system, either as part of pharmacologic or off-target activity, its evaluation for potential autoimmunity induction by using a specific... 

A few examples of animal models used in immunotoxicologic testing of drugs include Brown Norway rat and Lewis rat models, which are described in detail below. Other established mouse models of autoimmune diseases, e.g.,systemic lupus erythematosus, collagen-induced arthritis,pristane-induced arthritis and systemic scleroderma, may be considered for potential application in immunotoxicology evaluation. 

Based on the short overview of the known animal models relevant to autoimmune diseases, it is quite clear the task of hazard identification and risk assessment for potential drug-induced autoimmunity is presently very difficult. There is no single in vivo model that can be used routinely to evaluate new drugs for autoimmunity induction. Nevertheless, some of the models could possibly be applied to test therapeutics with specific properties (e.g., off-target immunoregulatory activity) and concerns (e.g., patient population) in order to gain additional perspective and understanding of their role in autoimmune responses. 

The described three cases address stimulation of the immune system by vaccines and/or adjuvants that could theoretically lead to adverse effects, including the potential induction of a systemic inflammatory response by new molecular adjuvants, T cell-mediated cytotoxicity by therapeutic vaccines, and autoimmunity by therapeutic cancer vaccines. In each case, the risk can be evaluated via appropriate assessments in nonclinical toxicity studies and by considerations of the relevance of the animal models to humans. 

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