Protein Therapeutics: The Immunogenicity Risk

Most therapeutic proteins, both in clinical trials and on the market, are, to a variable extent, immunogenic. Formation of anti-drug antibodies poses a risk that should be assessed during drug development, as it potentially compromises drug safety and alters such drug characteristics as pharmacokinetics and bioavailability. Immunogenicity risk assessment is dependent on the nature of the protein therapeutic, and should be analysed on a case-by-case basis. This article gives an overview of some of the factors central to estimating the likelihood and severity of immunogenicity of a protein therapeutic.

The immune system has evolved to protect hosts against foreign antigens – the host should differentiate ‘self’ from ‘nonself’ antigens. Immunogenicity is the immune response a host mounts against an antigen, such as a protein therapeutic. Typically, immunogenicity is characterised by measuring the production of anti-drug antibodies (ADA) against the protein therapeutic. Experimental evidence from the fast growing number of therapeutic proteins indicates that most administered proteins may induce ADA to some extent. These ADA can have an impact on drug characteristics, including the pharmacokinetics, bioavailability and drug clearance rate.

Whilst in many cases the ADA are non-neutralising antibodies, there are many documented cases where the immunogenicity gives rise to neutralising anti-drug antibodies (NAb). These NAbs have a direct effect on the drugs’ function. Apart from the likelihood of observing immunogenicity, the severity of this response has to be evaluated on a case-by-case basis, as the immune response ranges from a transient appearance of ADA with no clinical effect to severe lifethreatening conditions. Both industry and regulatory are currently developing immunogenicity risk assessment strategies for protein therapeutics.