Which Factors affects Immunogenicity? – Factors affecting Immunogenicity

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Immunogenicity is the inherent ability of a substance to produce an immune response inside the body. It may be a vaccine, biotherapeutic drug, therapeutic protein, or any foreign substance. It is mainly related with the recognition of that substance by the immune system.

During this process, the body can form antigen-specific humoral response and cellular response. Humoral response is mainly antibody based response. Cellular response is mediated by immune cells against the antigen.

Immunogenicity may be useful or harmful. In case of vaccines, it is a desirable property because it helps the body to build protection against a particular pathogen. So here immunogenicity is the main clinical aim.

In case of therapeutic proteins and biologic drugs, immunogenicity is mostly unwanted. The immune system may identify the biologic drug as a foreign substance. Then it produces anti-drug antibodies (ADAs) against the drug.

These ADAs can neutralize the activity of the drug. They may also change the clearance of the drug from systemic circulation. In some cases, it may cause safety problems and adverse clinical outcome in the patient.

Properties of Immunogen

The following are some important properties of immunogen–

  • An immunogen should be foreign to the host body. More difference from host protein, more strong immune response is produced.
  • The molecular structure of immunogen is important. Its amino acid sequence, physical structure and chemical nature help in recognition by immune system.
  • The protein molecule may form aggregates. These protein aggregates are large and repeated structure, so they can stimulate immune system strongly.
  • Some changes may occur after protein formation. These are called post-translational modifications (PTMs). Non-human glycans are easily recognized as foreign by immune system.
  • During storage or manufacturing, protein may get chemically degraded. Oxidation and deamidation can change protein shape and form new foreign region called neoepitopes.
  • Some impurities may also increase immunogenicity. Host cell proteins, trace chemicals and leachables may act as danger signals and stimulate immune response.

Factors affects Immunogenicity

The factors affecting immunogenicity are grouped as follows-

  • Protein aggregation– The protein molecules may clump together and form large multimeric structure. These aggregates can strongly trigger the immune system.
  • Primary sequence and foreignness– The amino acid sequence of therapeutic protein may differ from normal human protein. More foreign sequence can produce more immune response.
  • Post-translational modifications (PTMs)– Some structural changes occur during manufacturing. Non-human sugar structure or glycans may be added and it is recognized as foreign by immune system.
  • Degradation– The protein may be chemically changed during production or storage. Oxidation and deamidation can change the protein shape and expose new immune stimulating sites.
  • Impurities and formulation leachables– Trace contaminants, host cell proteins, and chemicals from rubber stopper or glass syringe may be present. These act as danger signals and stimulate immune response.
  • Genetics and HLA type– The genetic nature of patient affects immunogenicity. Human Leukocyte Antigen (HLA) alleles decide how drug fragments are bind and presented to immune cells.
  • Baseline tolerance and mutations– Some patients produce the target protein naturally, so tolerance is present. But in severe null mutation, the protein is absent and therapeutic protein may be recognized as foreign.
  • Age and gender– Age and sex of patient affects immune function. Hormone signalling and number of naive and memory immune cells may be different in different patient.
  • Underlying disease and immune status– The disease condition also affects immunogenicity. In autoimmune disease, immunocompromised condition or other immune disorder, immune response may be changed.
  • Route of administration– The way of drug entry into the body affects immune response. Subcutaneous injection generally has more immunogenic risk than intravenous infusion.
  • Dosing regimen and duration– Dose amount, frequency and treatment period affects immunogenicity. Episodic or on-demand dosing is usually more immunogenic than continuous prophylactic treatment.
  • Concomitant therapy– Other drugs given with therapeutic protein may change immune response. Immunosuppressant drugs can suppress immune response and reduce formation of anti-drug antibodies (ADAs).

D. Mode of action (MOA)

  • Drug target– The working mechanism of biologic drug also affects immunogenicity. If the drug target, stimulate or inhibit immune system components, then immune response may be increased or changed.
Factors affects Immunogenicity
Factors affects Immunogenicity

Significance of Immunogenicity

The following are some important significance of immunogenicity–

  • Vaccine efficacy– In vaccines, immunogenicity is useful property. It shows that body can produce protective immune response against an infectious disease. So it is taken as main clinical end point in vaccine study.
  • Therapeutic effect– In biopharmaceuticals, immunogenicity is usually unwanted. Anti-drug antibodies (ADAs) may bind with the therapeutic protein. As a result drug action become low or sometimes it is completely blocked.
  • Drug clearance– ADAs may combine with the drug and form circulating immune complex. These complexes are cleared fast from the body. So the amount of drug present in blood become less.
  • Drug behaviour– Immunogenicity can change pharmacokinetics and pharmacodynamics of drug. The drug may not remain in body for proper time. Its effect also become unpredictable.
  • Adverse reaction– Immune response against therapeutic protein may cause local or systemic reaction. It may be mild allergy, hypersensitivity, infusion reaction or severe anaphylaxis.
  • Autoimmune reaction– Sometimes ADAs may cross react with natural body proteins. This may block normal physiological function. It can cause serious condition like antibody mediated Pure Red Cell Aplasia (PRCA).
  • Regulatory need– Immunogenicity assessment is needed for approval of biologic drugs and biosimilars. Authorities like FDA and EMA ask for risk based immunogenicity testing for safety and efficacy.
  • Dose adjustment– Monitoring of immunogenicity helps to know how much immune response is produced and how long it remains. It helps in changing dose schedule and finding treatment failure in patient.
  • Patient safety– Study of immunogenicity is important to reduce risk in patient. It helps to plan safer treatment and avoid serious immune related problems.

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