Immunogenicity assessing

Committee for Medicinal Products for Human Use (CHMP), 2006. Concept Paper on Guideline on Immunogenicity assessment of Therapeutic Proteins. http //www. emea.eu.int/pdfs/human/biosimilar/24651105en.pdf... 

Currently, the various regulatory documents recommend the need for immunogenicity assessment, but the recommendations on Nab assays may vary between documents. Due to the lack of detail or clarity of intent for immunogenicity assessment, different companies may have different interpretations of the expectations for immunogenicity testing, leading to different approaches between companies. 

HCV peptide vaccine alone, or poly-L-argi-nine alone. All patients received six vaccinations at monthly intervals, with immunogenicity assessed at each time point and at 3 and 6 months after the last vaccination. 

Standardization and Testing". RequHemeats are geaerally specified within Hceases Hi the United States, and include a variety of Hi-process tests to assess purity, safety, and potency of the iadividual components and potency and safety of the final product. Potency is standardized by determining the size of the conjugate and the quantitative amount of saccharide that is bound to the carrier protein. General safety and immunogenicity is assessed Hi animals. 

Geng, D., Shankar, G., Schantz, A., Rajadhyaksha, M., Davis, H., and Wagner, C. 2005. Validation of immunoassays used to assess immunogenicity to therapeutic monoclonal antibodies. Journal of Pharmaceutical and Biomedical Analysis 39, 364-375. 

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

Regulatory guidance for the conduct of clinical trials on vaccines is specific. Traditional phase I trials in normal volunteers are not conducted. Rather, all trials assess not only safety but also efficacy (or at least immunogenicity). Trials may well be challenge trials, that is, after immunization subjects are purposely challenged with exposure to the infective agent of concern. 

There may be situations which warrant an assessment of carcinogenic potential, but immunogenicity and species specificity may preclude a two-year rodent bioassay. It may be necessary to develop in vitro assays to address a particular concern. For example, growth factors which may have the potential to support or stimulate the growth of transformed cells should be assessed for their ability to promote growth of either malignant or normal cells. 

Immunogenicity Nine percent of patients treated with peginterferon alfa-2a with or without ribavirin tablets developed binding antibodies to interferon alfa-2a, as assessed by an ELISA assay. The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown. 

In addition to the pivotal studies, several publications (Table 6.2) used other methods to test the response of individuals with celiac disease who were introduced to oats. These studies did not fulfill the selection criteria of pivotal studies namely an in vivo oats challenge with an intestinal/skin biopsy to assess the biological response to the introduction of oats into an otherwise gluten-free diet. Instead, they used various in vitro techniques to assess the immune response to avenin, or serology without an intestinal mucosal biopsy. Most of the methods used duodenal mucosal cultures prepared from biopsies or intestinal T cell lines obtained from individuals with celiac disease. Other studies measured the immunogenic reaction in peripheral lymphocytes or measured the presence of various antibodies in individuals with verified celiac disease who included oats in their diet, in comparison with a reference group (Table 6.2). Some of these studies used patients that were previously included in pivotal studies. These studies are identified with an asterisk ( ) in Table 6.2. 

It is the physician s responsibility to inform the patient of the risk of immunization and to use vaccines and antisera in an appropriate manner. This may require skin testing to assess the risk of an untoward reaction. Some of the risks previously described are, however, currently unavoidable on the balance, the patient and society are clearly better off accepting the risks for routinely administered immunogens (eg, influenza and tetanus vaccines). 

Considerable research has been devoted to assessment of the immunogenicity of HPMA copolymers.108-110 By themselves, HPMA copolymers do not elicit any immune response. When HPMA copolymers were modified with oligopeptides, only weak immunogenic responses were observed, and their intensity depended on the structure of the oligopeptide sequence and the host.111... 

There are many techniques that can be employed to assess the immuno-genicity of a vaccine candidate, and laboratories interested in pursuing this objective should also explore other assays suited to their purposes. In this model, vaccine immunogenicity is measured by determining levels of anti-LHRH antibodies induced in mice immunized with lipopeptide or a nonlipi-dated peptide control. It is important to correlate vaccine immunogenicity with biological function, and we measure the reproductively capability of vaccinated female mice as an indication of vaccine efficacy. Techniques that determine testosterone and oestrogen levels are also useful. 

---