Unintended immunosuppression

Figure 3.3.1-2 Application of the TDAR assay in immunotoxicity assessment. When evaluating unintended immunosuppression, the TDAR assay may be conducted when evidence of immunotoxicity is seen in repeated-dose toxicity studies. In these instances, the assay should be conducted prior to Phase 3 or earlier, depending on factors such as the severity of the findings and the intended patient population. The TDAR assay also could be used early in the drug development process to screen for immunotoxicity potential. This approach may be useful particularly to help de-risk unintended off-target immunomodulation or when a novel target/mechanisms may alter immune function.

The objective of this section is to provide a description of several immune parameters and methodologies that are used in the preclinical setting to characterize immune hazards for human risk assessments. The utility of a standalone functional evaluation, specifically the rat T cell-dependent antibody response (TDAR) model developed for regulated immunotoxicity evaluations (Gore et al, 2004), is mainly used for hazard identification, i.e., unintended immunosuppression. This assay is based on an end point parameter that is the... 

A major difficulty with any of these assays is their lack of sensitivity to demonstrate mild to moderate changes in immune function. These assays are typically used for the diagnosis of primary or acquired immune deficiency when one given arm of the immune response is thought to be profoundly affected. Otherwise, there is a wide physiological range in response in these assays so that defects caused by treatment or exposure to unintended immunosuppressive drugs are likely to be missed or overlooked. In fact, the same situation is found in preclinical immunotoxicity studies. 

The main adverse clinical consequences of drug-induced immunosuppression either unintended or expected include infectious complications and more frequent neoplasias (Luebke et al., 2004 Descotes, 2005). Infections in this setting may be more frequent, often more severe and relapsing, and sometimes atypical ( opportunistic infections ). More frequent neoplasias in immunocompromised patients are typically virus-associated neoplasias, either lymphoma or skin cancers (Vial and Descotes, 2007). The mechanisms involved in the impaired resistance of the host toward pathogens are manifold they can affect the innate or adaptive immune responses or both. 

Immunostimulation caused by a drug candidate, as well as immunosuppression can be either unintended or expected. Although the clinical consequences of immunostimulation or immune activation have been largely overlooked until the widely publicized TGN1412 story (Suntharalingam et al., 2006), they have... 

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