Immunogenicity of biologic agents

Biologics have become a core component of many treatment strategies for rheumatic inflammation. Scientists often consider that immunogenicity is the important limiting factor in the early stages of development of biological agents. However, theoretical guidance is relatively limited and the determination methods for measuring immunogenicity are complex, making the development of past research difficult. But now, the emergence of biosimilars has sparked new interest in immunogenicity, the development of more accurate and convenient testing methods, a greater understanding of the pharmacokinetic results of immunogenicity, and comprehensive and specific guidelines from regulators. Rheumatologists’ overall understanding of the field has greatly improved, including the factors that cause the immunogenicity, the potential clinical consequences, and the impact on daily treatment.

All biological agents are immunogenic and many pathways affect their bioavailability, including patient-specific factors, disease-specific characteristics, and genetic background.

Factors affecting the immunogenicity of biological agents:

Target antigen:

• solubility

• Whether it binds to the cell

Biological agent molecules:

• Sequence: mouse or human sequence

• Sexual dimorphism

• Structure: glycosylation or other post-translational modifications

Biological products:

• preparation

• dose

• Delivery way

• Dosing frequency

• Aggregates and impurities

Patient:

• Disease types

• Disease activity

• Concomitant therapy

• Genetic factors

In theory, humanized antibodies should have lower immunogenicity than chimeric antibodies because there are fewer non-human protein sequences in the variable region that might be considered foreign. Infliximab (the only chimeric monoclonal antibody among the five available TNF inhibitors) is more immunogenic than the other four TNF inhibitors. The debate over the immunogenicity of chimeric, humanized, and fully humanized antibodies has been going on for a long time, and the data reviewed in this paper suggest that the immunogenicity of fully humanized antibodies may be the lowest. See the table below:

Frequency of anti-drug antibody formation in rheumatic diseases

The detection and evaluation of ADAs is a complex process and the results may be influenced by the analytical methods used. Therefore, it is important to use specific and approved strategies when evaluating immune responses. The screening test must be sensitive, specific, and able to identify all ADAs subtypes of a given biologic agent. Immunogenicity was assessed by different types of immunoassays, such as enzyme-linked immunosorption assays (ELISAs), electrochemical luminescence immunoassays (ECLIAs), and radioimmunoassays, as well as by different forms of immunoassays, such as direct, indirect, bridging, and competitive forms. The chart below shows the commonly used forms of immunoassay for anti-drug antibody (ADA) tests and their advantages and disadvantages.

commonly used forms of immunoassay for anti-drug antibody (ADA) tests and their advantages and disadvantages

Reference：

Strand, V., Goncalves, J. & Isaacs, J.D. Immunogenicity of biologic agents in rheumatology. Nat Rev Rheumatol 17, 81–97 (2021). https://doi.org/10.1038/s41584-020-00540-8

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