Immune toxicity study

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. In the context of new chemical entities (NCEs, i.e. low molecular weight traditional chemicals), not only can the drug itself exhibit a toxic effect, but so potentially can drug breakdown products. As proteins are degraded to amino acids, any potentially toxicity associated with protein-based drugs is typically associated with the protein itself and not degradation products. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

Wolfe GW, Layton KA (2003) Multigeneration reproduction toxicity study in rats (unaudited draft) diethylhexylphthaiate muitigenerational reproductive assessment when administered to Sprague-Dawley rats in the diet. The Immune Research Corporation (Gaithersburg, Maryland), TRC Study no 7244-200... 

As shown in Figure 2-4, there is a considerable body of data on the health effects of carbon tetrachloride in humans, especially following acute oral or inhalation exposures. Although many of the available reports lack quantitative information on exposure levels, the data are sufficient to derive approximate values for safe exposure levels. There is limited information on the effects of intermediate or chronic inhalation exposure in the workplace, but there are essentially no data on longer-term oral exposure of humans to carbon tetrachloride, most toxicity studies have focuses on the main systemic effects of obvious clinical significance (hepatotoxicity, renal toxicity, central nervous system depression). There are data on the effects of carbon tetrachloride on the immune system, but there are no reports that establish whether or not developmental, reproductive, genotoxic, or carcinogenic effects occur in humans exposed to carbon tetrachloride. 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, while in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. 

Biotechnology-derived vaccines that do not induce an immune response in lower species may have to be tested in a primate species, such as the cynomolgus monkey. A study design in the monkey has been suggested for this purpose (6), based on a proposed developmental toxicity study design for monoclonal antibodies (7). 

There should be an extension of research into the analysis of human body fluids, e.g. blood, urine, milk by way of adducts specific to the perceived most harmful mycotoxins. There should also be continued examination of novel ways of determining toxic effects on the immune system. The use of human cell lines for toxicity studies should be further developed especially using cells that have been transfected with human cytochromes. 

Since many biotechnology products are designed to modulate the immune system, basic immunotoxicity parameters have traditionally been evaluated as part of standard toxicity studies. Over time more and more immunotoxicity specific parameters have been validated in toxicology species, including primates. These parameters (humoral and cell-mediated) should be measured as appropriate. Other specific issues for biopharmaceuticals include immunogenicity, as previously discussed. 

Immunogenicity is an important issue to consider for biopharmaceuticals as it can limit toxicity testing. An immune response to the biopharmaceutical is expected because the test agents are human proteins administered to animals, and the response can limit the duration of the toxicity studies. Antibodies to a test agent can neutralize its activity and thus reduce exposure. In addition antidrug antibodies can potentially cause toxicity such as deposition of immune complexes in the kidney. This issue is discussed further in Chapter 10. 

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