What Are the Importance and Relevant Methods of Immunogenicity Prediction & Asse

Posted by Jerry Carter on June 15th, 2019

Immunogenicity of drugs refers to the nature of drugs that stimulates the body to form specific antibodies or sensitized lymphocytes. Prediction and evaluation of antibody immunogenicity are significant sections of biotechnological drug application for clinical trials and registration. Immunogenicity, as one of the decisive factors in the development of biotechnological drugs in animal models, although is not necessarily expected to occur in humans, yet it is important to evaluate and predict drug-induced immune responses. Anti-drug antibodies may neutralize drug activity, affect drug clearance, plasma half-life and tissue distribution, alter pharmacodynamics/pharmacokinetics, so that the effects observed in non-clinical studies may not be the real pharmacological and/or toxic reactions of drugs. Therefore, the immunogenicity assessment of drugs must be conducted simultaneously when evaluating their safety.

With the development of a large number of bio-tech antibody drug types, the prediction of immunogenic reaction has become a key factor in elucidating the clinical safety and efficacy. Complete immunogenicity assessment & prediction should be methodologically verified by selecting reasonable immunological and biological methods to detect changes in antibody titer and analyze antibody subtypes and characteristics, to determine the neutralizing activity of antibodies, and to form and deposit immune complexes. The current challenge in immunogenicity assessment lies in the optimization of antibody immunogenicity prediction methods and the predictability of animal and in vitro models. 

1. Factors influencing immunogenicity

Many factors can influence the immunogenicity of biotech drugs, such as protein structure (sequence and glycosylation, etc.), downstream processing, storage conditions (oxidation-induced degeneration and aggregation), contamination or impurities, dose, time and route of administration, formulation, packaging materials and genetic specificity of the patient, etc. As for the antibody immunogenicity, relevant factors are as many too, including delivery route, delivery vehicle, dose regimen, aggregation, innate immune system activation and the capacity of the protein to interface with the humoral (B cell) and cellular (T cell) immune systems. To predict immunogenicity through analysis of proteins and antibodies, T-cell Epitope Prediction & B-cell Epitope Prediction are two main methods adopted by scientists utilizing in silico technologies presently. Generally speaking, it is impossible to accurately predict the incidence of clinical immunogenicity in the current technical context, but the approximate correlation between pre-clinical immunogenicity prediction (T/B epitope prediction and in vitro T cell test) and clinical immunogenicity can help us reduce the risk of high immunogenicity and avoid this "deep-water bomb" as far as possible. It is hopeful that more precise methods can be developed sooner or later.

2. Methods of reducing antibody immunogenicity

With the advancement in tech, there emerge many strategies utilized in order to reduce the immunogenicity, and scientists have succeeded in replacing animal sequence with human sequence or not using animal source (such as recombinant human insulin and monoclonal antibody) or improving the manufacturing process and purity. For example, NMR spectroscopy that is developed in recent years, makes the identification work of antibody epitopes relatively convenient. Since antibody epitopes often locate at a small number of discrete sites on the surface of the protein, and the binding affinity of the antibody depends only on the interaction of a small number of amino acid residues, changes in key amino acids in the antibody epitope can reduce the binding of existing antibodies hence.

In the stages of research and development, the methods of calculation and experiment are combined to reduce the immunogenicity as much as possible, and also the traditional and new immunogenicity detection methods are united to conduct immunogenicity prediction of various mutants. As a result, it is highly possible to develop stable, powerful and weak immunogenic biotechnological drugs in the near future.