The advent of the era of precision medicine takes monoclonal antibody (mAb) drugs that have high specificity and effectiveness to a hot spot in biological drug therapy.

In 1975, Georges Köhler and César Milstein successfully invented hybridoma technology, laying the foundation for monoclonal antibodies. In 1986, the first mouse mAb drug Muromonab-CD3 (orthoclone OKT3, Janssen-Cilag) was approved by the FDA. However, because of its strong immunogenicity, it produced human anti-murine antibodies (HAMA) that led to rapid drug clearance, with a half-life of only a few hours to more than ten hours, greatly limited clinical use.

In recent years, immunogenicity issues gradually surfaced as the popularization of mAb drugs. For patients, immunogenicity affects the safety and effectiveness of drugs, and may even cause new fatal diseases because of the crossover of anti-drug antibodies and endogenous proteins. For pharmaceutical companies, if immunogenicity problems are discovered in the late stage of clinical development, they will suffer heavy losses. For the drug regulatory department, immunogenicity is also the top priority. All biological drugs must have immunogenicity assessment to ensure the safety and effectiveness before they are marketed.

Anti-drug antibody (ADA) is the main approach of evaluating antibody drug immunogenicity. There are two mechanisms of ADA production. One is that the body treats antibody drugs as foreign proteins (such as first-generation murine antibodies and chimeric antibodies) to produce a strong immune response, which is similar with vaccine immunization. The other is that the body's tolerance mechanism of self-proteins (such as fully human antibodies) is destroyed, likely the mechanism of autoantibody production in autoimmune diseases. Generally, the formation of ADA can be divided into patient-related factors and drug-related factors.

Patient-related factors:
* Genetic factors
* Patient's disease state
* Dosing regimen

Drug-related factors
* Antibody source: chimeric antibodies, humanized antibodies, and fully human monoclonal antibodies, etc.
* Recipe, container system, storage conditions
* Changed glycosylation patterns and atypical glycosylation patterns
* Impurities produced by production method, route, dosage, frequency of administration, etc.

The possible clinical consequences of ADA include loss or reduction of efficacy, local reactions, serum sickness or immune complex-mediated diseases, and major allergic reactions (such as urticaria, bronchospasm, and bronchoconstriction). It is worth noting that induced ADAs present in both serum and various organs. Therefore, it is very important to measure antibody levels, PK, PD markers, efficacy, and safety simultaneously and repeatedly during clinical treatment.

Generally, IgG is the most common type of ADA induction. In some cases, low-affinity IgM antibodies can also be induced. If the mAb contains a non-human carbohydrate structure, IgE testing for the patient is necessary. Another example that should be considered for IgE testing is the high incidence of allergic reactions at the first dose in the early clinical stages of product development.

ADAs ( are widely applied in the detection and quantification of therapeutic antibodies during the drug development process, such as pharmacokinetic and immunogenicity assays, which is conducive to exacter assessment of the exposure-response relationship to determine the optimal dose and safety parameters, compared with general ligand binding assays. Moreover, ADA can also be used as a reference for immunogenicity assays owing to their ability to bind to antibody drugs specifically. Commonly used ADAs are:

* Anti-idiotype antibodies for PK assay
* Anti-idiotype antibodies for ADA assay
* Anti-idiotype antibodies for neutralizing assay
* Anti-ADC antibodies

There are three criteria for mAb drugs for clinical use to follow, which are specificity, stability, and low or no immunogenicity. Among them, the immunogenicity of antibody drugs is the most important factor limiting the efficacy of antibody drugs, and it is also the most difficult problem to overcome in the development process. The iteration of antibody drugs mainly aims at reducing the immunogenicity.

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