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Many biotechnology-derived pharmaceuticals intended for human are immunogenic in animals. The induction of antibody formation in animals is not predictive of a potential for antibody formation in humans. Nevertheless, humans may develop serum antibodies against humanised and fully human proteins, and frequently the therapeutic response persists in their presence. One must carefully interpret an ensemble of data sets in order to properly evaluate the impact of the therapeutic on the immune system and vice-versa.

From ICH S6 we can read the following:

“Immunotoxicity studies

One aspect of immunotoxicological evaluation includes assessment of potential immunogenicity (see section 3.6). Many biotechnology-derived pharmaceuticals are intended to stimulate or suppress the immune system and therefore may affect not only humoral but also cell-mediated immunity. Inflammatory reactions at the injection site may be indicative of a stimulatory response. It is important, however, to recognise that simple injection trauma and/or specific toxic effects caused by the formulation vehicle may also result in toxic changes at the injection site. 

Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 

The expression of surface antigens on target cells may be altered, which has implications for autoimmune potential. Immunotoxicological testing strategies may require screening studies followed by mechanistic studies to clarify such issues. Routine tiered testing approaches or standard testing batteries, however, are not recommended for biotechnology-derived pharmaceuticals.” 

The ICH S8 document states the following:

“Evaluation of potential adverse effects of human pharmaceuticals on the immune system should be incorporated into standard drug development. Toxicity to the immune system encompasses a variety of adverse effects. These include suppression or enhancement of the immune response. Suppression of the immune response can lead to decreased host resistance to infectious agents or tumor cells. Enhancing the immune response can exaggerate autoimmune diseases or hypersensitivity. Drug or drug-protein adducts might also be recognized as foreign and stimulate an anti-drug response. Subsequent exposures to the drug can lead to hypersensitivity (allergic) reactions. Much of the science and method development and validation efforts in the past have been focused on evaluating drug development candidates for their potential for either immunosuppression or contact sensitization. No standard approaches for human pharmaceuticals are currently available for testing for respiratory or systemic allergenicity (antigenicity) or drug-specific autoimmunity; testing for these endpoints is not currently required in any region. There are no regional differences in testing approaches of skin sensitization.

Immunosuppression or enhancement can be associated with two distinct groups: 1) Drugs intended to modulate immune function for therapeutic purposes (e.g., to prevent organ transplant rejection) where adverse immunosuppression can be considered exaggerated pharmacodynamics; 2) Drugs not intended to affect immune function but cause immunotoxicity due, for instance, to necrosis or apoptosis of immune cells or interaction with cellular receptors shared by both target tissues and non-target immune system cells. Anti-proliferative agents used to treat cancer are an example of drugs that produce unintended immunosuppression. In such instances, adverse findings in nonclinical studies are predictive of human immunotoxicity in a rather straightforward manner. That is, specific assays to determine immunotoxicity are probably not valuable in drug risk assessment since the target tissues are usually rapidly dividing cell types, such as bone marrow-derived immune system progenitor cells. Hence, the adverse effects on immune function can be predicted based on pharmacologic activity and can usually be reliably evaluated in non-clinical studies. For other types of compounds not intended to suppress the immune response, distinction between exaggerated pharmacodynamics and non-target effects can be less obvious. As an example, some anti-inflammatory compounds have an effect on certain innate immune functions but do not necessarily affect the adaptive immune response.”

Standard Immunotox tests according to ICH S8:

1. Total leukocytes counts and absolute differential leukocytes counts (levels of Ig);
2. GLP assays:

  • T-cell dependant antibody response (TDAR);
  • Immunophenotyping;
  • NK assays;
  • Host resistance studies;
  • Macrophage / Neutrophil Functions;
  • Assays to measure cell-mediated immunity

Factors to consider that might prompt additional immunotoxicity studies can be identified in the following areas:

  • (1) findings from standard 28-day toxicology study (STS)
  • (2) the pharmacological properties of the drug
  • (3) the intended patient population
  • (4) structural similarities to known immunomodulators
  • (5) the disposition of the drug
  • (6) clinical information.

Additional Immunotox studies:

  • 1. CTL cytotoxicity
  • 2. Biomarkers expression
  • 3. Markers of apoptosis
  • 4. Immunohistochemistry.

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