Preclinical models used for immunogenicity prediction of therapeutic proteins.

All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.

[Immunogenicity of therapeutic antibodies]. / Immunogénicité de protéines d'intérêt thérapeutique : les anticorps monoclonaux thérapeutiques.

Unwanted immunogenicity, i.e., the developpement by patients of anti-drug antibodies is a significant problem with biologicals therapeutic reagents and can compromise clinical response. Over 20 antibodies currently on the market and over 100 drug candidates are currently in clinical trials; all therapeutic antibodies are showing some level of immunogenicity, and although it has been reduced with the advent of antibodies including human sequences, or even humanised antibodies, this concern will not be totally eradicated. Whereas the actual anti-drug response can only be addressed during clinical development or post-marketing, the industry and the regulatory instances are facing a challenge to develop accurate procedures for the assessment of immunogenicity related to antibody therapeutics, addressing both the likelihood and the severity of the drug-related immunogenicity. This review will discuss the multiple factors that can contribute to a potential immunogenicity of protein therapeutics patient/disease related, as well as related to the drug itself, and the strategies to identify anti-drug antibodies, both in clinical and non clinical assays.

Strategies for preclinical immunogenicity assessment of protein therapeutics.

The immunogenicity assessment of protein therapeutics has received significant attention, both from regulatory bodies and industry. With the advent of several industry white papers and the EMEA guidance on the clinical assessment of antidrug antibodies (ADAs), the immunogenicity screening framework has become better defined. Immunogenicity in many cases leads to the loss of efficacy of a drug, but can also lead to the production of severe adverse effects. A risk assessment should be conducted for every biotherapeutic under development to address the incidence rate of immunogenicity, as well as the severity of the adverse effects caused. Typically, immunogenicity is characterized by measuring the ADAs that occur in individuals exposed to a drug. Industry and academic research efforts are geared toward the assessment of potential immunogenicity in a preclinical setting, with the aim of predicting immunogenicity prior to clinical trials, and thereby reducing the attrition rate of drugs in clinical development. This article addresses the current status, strategies and challenges related to the predictive immunogenicity assessment of protein therapeutics.

Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine.

A patient with polymorphic ventricular tachycardia, long QT interval and conduction disorders secondary to long-term treatment with chloroquine is presented.

Immunogenicity screening in protein drug development.

Most therapeutic proteins in clinical trials or on the market are, to a variable extent, immunogenic. Formation of antidrug antibodies poses a risk that should be assessed during drug development, as it possibly compromises drug safety and alters pharmacokinetics. The generation of these antibodies is critically dependent on the presence of T helper cell epitopes, which have classically been identified by in vitro methods using blood cells from human donors. As a novel development, in silico methods that identify T cell epitopes have been coming on line. These methods are relatively inexpensive and allow the mapping of epitopes from virtually all human leukocyte antigen molecules derived from a wide genetic background. In vitro assays remain important, but guided by in silico data they can focus on selected peptides and human leukocyte antigen haplotypes, thereby significantly reducing time and cost.