Why Immunogenicity Test of Biopharmaceuticals Is Essential?

Posted by Ellen Burns on November 1st, 2019

What is immunogenicity

Immunogenicity refers to the characteristics that can stimulate the body's immune system to cause an immune response. Immunogenicity is one of the characteristics of antigen, it can act on the antigen recognition receptors of T lymphocytes and B lymphocytes to make them proliferate and differentiate, and thus producing immune effectors, such as specific antibodies and sensitized lymphocytes. The strength of immunogenicity is usually related to molecular weight, size and chemical structure. For the substances with immunogenicity, generally speaking, the larger the molecular weight is, the stronger the immunogenicity is. If the molecular weight is less than 4000, they are generally not immunogenic. If the molecular weight is between 4000 and 10000, they are weakly immunogenic. And if the molecular weight is higher than 10000, they have strong immunogenicity. Exceptions also exist, such as gelatin, which have a molecular weight of 100,000 but are still weakly immunogenic, because they are linear chain amino acid structures that are susceptible to degradation.

Immunogenicity of biopharmaceuticals

Immunogenicity testing is an essential step in the antibody drug development process and needs to be carried out at both preclinical and clinical stages. Immunogenic drugs may induce harmful immune responses and can form anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs). The former will cause a strong immune response in patients, and even endanger the lives of patients; the latter can neutralize the ability, inhibit the biological activity of biopharmaceuticals and reduce their efficacy. Therefore, considering that immunogenicity will seriously affect the efficacy and safety of the drug, FDA and other drug regulatory authorities require that all biopharmaceuticals should be tested for immunogenicity. But today's predictions are poor, and many drugs do not detect ADA problems until clinical phase III. For enterprises, this undoubtedly increases R & D risk and capital investment.

Sources of immunogenicity of biopharmaceuticals

There are two main sources of immunogenicity of biopharmaceuticals: endogenous and exogenous. Endogenous immunogenicity results from nonhuman amino acid sequences, different human amino acid sequences, and modifications (e.g., point mutations, glycosyl modifications, trehalose, fatty acids, PEGylation, Fc fusions, bispecific antibodies, and multifunctional antibodies) to enhance efficacy or prolong half-life, which should be considered early in drug development. The exogenous immunogenicity mainly comes from CMC (CMC mainly refers to manufacturing process, impurity study and quality study), materials and transportation. For example, increasing antibody expression without keeping up with glycosylation leads to the production of multimers, which are one of the important causes of immunogenicity. For another example, common surfactants can cause a strong immune response. Alternatively, the route, frequency, and timing of administration may also affect the immunogenicity of the protein.

How to detect immunogenicity of biopharmaceuticals

FDA recommends that immunogenicity risk testing be conducted preferably during the IND phase and clinical phase I. For biopharmaceuticals with high immunogenicity risk, pharmaceutical companies should conduct pre-validation at an early stage and conduct real-time detection and analysis before the samples are cryopreserved.