A Risk-Based Approach to Immunogenicity Concerns of Therapeutic Protein Products, Part 2: Considering Host-Specific and Product-Specific Factors Impacting Immunogenicity - For protein therapeutics, im

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A Risk-Based Approach to Immunogenicity Concerns of Therapeutic Protein Products, Part 2: Considering Host-Specific and Product-Specific Factors Impacting Immunogenicity
For protein therapeutics, immunogenicity testing should be conducted from the earliest stages of product development.


BioPharm International




Because all protein therapeutics are potentially immunogenic, FDA has developed a risk assessment strategy for novel products in development and for major changes in manufacture and clinical use of licensed products. The first part of this series (BioPharm International, November 2004) discussed FDA's assessment of critical factors regarding the consequences of immune responses to protein therapeutics. These factors were based on product origin (such as xenobiotic and mammalian cell) and the presence and biological function of endogenous protein counterparts. In this second part, host-specific and product-specific factors that positively or negatively impact immunogenicity are discussed.

RISK ASSESMENT STRATEGY Second Element: Consider Host-Specific Factors that Impact Immunogenicity Positively or Negatively.

Immunologic status and competence of the host. This is a critical factor in considering the risk of immune responses to therapeutic proteins. The incidence of hypersensitivity responses to specific biological drugs may be strongly affected by treatment of patients with steroids and concomitant treatment with chemotherapeutic agents.2 However, the incidence of hypersensitivity responses to drugs and environmental antigens does not appear to be diminished by intensive chemotherapy, despite the reduction of lymphocytes,30 although formal studies are lacking. However, patients who are undergoing chemotherapy or chemoradiotherapy are at much lower risk of mounting binding and neutralizing-antibody responses. This may be due to the severe depletion of CD4+ T cells which are replenished slowly and are required for development of T-dependent IgG antibody responses.31 For example, 95% of immune competent cancer patients generated neutralizing antibody to GM-CSF, while only 10% of immune-compromised cancer patients did so.32 Similarly, 4% of healthy volunteers mounted neutralizing antibody responses against a pegylated, truncated MGDF, while only 0.5% of cancer patients did so.10

In view of the relatively high incidence of food allergy directed to plant allergens, consideration should be given to the possibility of engendering hypersensitivity responses in patients treated with products derived from bioengineered plants bearing an allergen to which they are sensitive. Although this is currently a theoretical concern, the agency has anticipated this possibility due to the increasing exploration of plants as substrates for production of vaccines and biological therapeutics and has offered guidance.33

Route of administration. Subcutaneous (SC) administration is known to engender immune responses far more ably than either the intramuscular (IM) or intravenous (IV) routes. This may be due to the rapid egress of the product into tissues containing a high frequency of potent antigen presenting cells (APCs); the potential for product to form or stay in aggregates in the SC space compared to dispersal of aggregates in the high-flow, fluid-rich IV environment; and to the possible depot effect of SC injection. The increased incidence of pure red cell aplasia (PRCA) mediated by neutralizing antibodies to Eprex is a good case in point; it appears that the SC route is necessary, though not sufficient, to generate neutralizing antibody.

Dose and frequency of administration. The effects of dose and frequency are not independent of other factors such as route of administration, product origin, and product-related factors that influence immunogenicity. For example, one would expect that for foreign proteins, frequent administration would enhance immunogenicity, especially when given by a more immunogenic route. In contrast, frequent administration of high doses of protein intravenously induces tolerance to Factor VIII in those patients who are least tolerant. Product-related factors, such as the presence of adjuvant and the type and level of product aggregates, may be crucial in determining whether a given dosing regimen proves immunogenic.

Level of immune tolerance to endogenous protein. The completeness of immunologic tolerance to an endogenous protein determines how easily tolerance to it can be broken by administration of a therapeutic counterpart. Thus, tolerance in both the T- and B-cell partners required for IgG-antibody production depends on numerous factors, especially the abundance of the protein.34-36 In this regard, T cells are tolerized at lower levels of soluble self-proteins than B cells,34 due to multiple mechanisms for negative selection of antigen-specific T cells in the thymus, including promiscuous expression of tissue-specific antigens.37


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