Assay Development and Immunogenicity Testing

Immunogenicity is becoming an integral feature within drug development activities.

Testing immunogenicity, however, presents those within the pharmaceutical industry with a host of challenges; ones which must be overcome as developers look to produce an increasing number of biological therapies.

ProImmune, for example, recently identified the difficulties companies developing novel therapies have in integrating for measuring cellular immune responses within drug discovery while complying with Good Laboratory Practice and Good Clinical Practice guidelines.

Designing immunogenicity tests

Different approaches to immunogenicity are appropriate depending on the clinical trial taking place. However, the FDA identifies four key areas which should be considered when designed assays for immune response.

The tests must be sensitive enough to detect "clinically relevant" levels of antibodies. Due attention must be paid to the possibility of interference from the matrix or onboard products.

Risk-based application is another key consideration. "The risk to patients of mounting an immune response to product will vary with the product," the FDA said.

Developers must also evaluate any possible functional or physiological responses are a result of immunogenicity.

"Immune responses may have multiple effects including neutralising activity and ability to induce hypersensitivity responses, among others," the regulator said.

Under the current system, the FDA warns while each company's assays for determining immunogenicity are effective, they are often not comparable. It therefore recommends companies conduct head-to-head trials using a standardised test wherever possible.

Poor immunogenicity results can derail a clinical trial, and therefore there is increasing demand from both the industry and regulators for "robust evaluation of candidate protein drug immunogenicity at a preclinical stage," a recent article published in the journal Drug Discovery & Development noted.

Selecting the right assays

"Most biologics elicit some level of antibody response. Since this antibody response could lead to potentially serious side effects, it is necessary not only to screen for immunogenicity but also to quantify and characterise the antibody response," Edwin Merrifield, writing for Genetic Engineering a Biotechnology News, noted.

Merrifield explained there have been recommendations made for the development of anti-drug antibody (ADA) immunoassay for use within clinical trials.

He argued that while immunogenicity testing is important for monoclonal antibodies, it could be of even greater importance for different therapies.

"It can be expected that higher-risk emerging therapies will be evaluated for immunogenicity more frequently than lower-risk therapies," he added.

In the future these are likely to include biosimilar antibodies, which present a potentially large revenue stream for the pharmaceutical industry, but equally present problems in ensuring immunogenicity is comparable with the existing therapy.

The question as to whether immunogenicity testing should be outsourced is a difficult one for pharmaceutical companies. 

Specialist testing companies, such as ProImmune, are likely to have a greater number of standardised assays already developed, however there are concerns surrounding the complex regulation governing this area.

Late last year the company announced its assay services for measuring cell mediated immune responses were available in accordance with GLP and GCP, allowing companies to ensure their submissions complied with all guidelines.

With immunogenicity testing set to play an increasingly important role in drug development in the future, it is likely greater demand for such services will be seen.