Immunology services for the development
of novel medicines

Dr. Bernd Liedert on Immunogenicity Testing

In a FOCUS workshop at Heidelberg Technology Park Dr. Bernd Liedert of Merck Serono (Darmstadt, Germany) provided his views on a risk-based strategy for the assessment of immunogenicity directed against therapeutic proteins.

He started out with the fundamental 2004 citation of the FDA’s Dr. Amy Rosenberg that “All proteins are potentially immunogenic”. Immunogenicity results from two mechanisms, a reaction to neo-antigens and/or the breakdown of immune tolerance, whereby the latter is very much dependent on aggregate formation of the antigen. Aggregate formation allows direct B lymphocyte activation through cross-linking of surface-bound IgM / IgD containing B-cell receptors without the need for antigen-specific help by T lymphocytes.

Dr. Liedert put the topic into perspective by summarizing the potential consequences of anti-drug antibodies (ADAs): Although formation of these ADAs has no clinical consequences in most cases, a sometimes even dramatic impact on safety and/or efficacy cannot be ruled out (Fig. 1).

In the first major part of his presentation Dr. Liedert reviewed the current regulatory framework in Europe (EMA; Fig 2) and the US, whereby in the US a series of four white papers provided basic advices, which were recently compiled in a first FDA Guidance on assay development (Fig. 3). Dr. Liedert emphasized that analysis of immunogenicity is one essential pillar in the assessment of biosimilars and therefore part of corresponding regulations.

In the second part Dr. Liedert addressed the tiered concept of “screening” and “confirmatory” assays for immunogenicity testing and outlined some technical aspects and challenges of current anti-drug antibody assay formats (Figs. 4 and 5).

A major issue in the development process of a given therapeutic protein is assessment of its immunogenicity risk. To this end, Dr. Liedert provided his view on the evaluation of primary and secondary immunogenicity risk factors, which describe and rate clinical consequences and probability of anti-drug immune responses (Fig. 6 and 7). This evaluation then leads to allocation of the drug into a low / medium or high risk category.

The classification helps to define a risk-adapted immunogenicity testing strategy tailored to the specific compound (Fig. 8). Extent and frequency of testing has to be defined as well as degree of assay validation. Concomitant analysis of pharmacokinetics and monitoring of appropriate safety/efficacy marker might support association of positive findings with potential clinical consequences.

In most cases it is acceptable to analyze samples, collected for immunogenicity testing, after the end of a clinical trial. For therapeutic proteins, where immunogenicity-induced depletion of an unique endogenous counterpart is a serious concern, testing may be performed in real time and NAb-positivity may be defined as withdrawal criterion. In this case it should be warranted that the applied assays are capable to measure ADAs in the presence of drug (especially for protein-drugs with a long half-life).

Taken together, Dr. Liedert provided very valuable information derived from his hands-on experience in immunogenicity testing with a clear focus on decision making in specific development projects. He concluded by stating that “any immunogenicity strategy will always have to be adapted individually for each project” and that sponsors should not hesitate to seek Scientific Advice at the Health Authorities.

Disclaimer: The views expressed in this summary are the personal views of Dr. Bernd Liedert and may not be understood or quoted as being made on behalf of, or reflecting the position of Merck Serono.