Immunogenicity of therapeutic proteins: clinical implications and future prospects.

BACKGROUND: Therapeutic proteins have revolutionized the treatment of many diseases. In the near future, many more therapeutic proteins are likely to become available for an increasingly wide range of indications.
OBJECTIVES: This article reviews the incidence, causes, and consequences of formation of antibodies to therapeutic proteins and suggests ways to address issues surrounding immunogenicity.
METHODS: Searches of MEDLINE and EMBASE databases were performed, covering the period 1990 to May 2002. Search terms included immunogenicity, antibodies, and the names of specific therapeutic proteins and classes of therapeutic proteins. Bibliographies of retrieved articles were not searched.
RESULTS: All exogenous proteins, including therapeutic ones, have the potential to cause antibody formation. The reported incidence of antibody formation with therapeutic proteins varies widely between proteins and between studies (depending on the assay techniques used). The clinical consequences of antibody formation vary with the type of antibody present; for example, neutralizing antibodies are more likely to cause loss of efficacy than nonneutralizing antibodies. The immunogenicity of therapeutic proteins can be influenced by many factors, including the genetic background of the patient, the type of disease, the type of protein (human or nonhuman), the presence of conjugates or fragments, the route of administration, dose frequency, and duration of treatment. Manufacturing, handling, and storage can introduce contaminants, or alter the 3-dimensional structure of the protein via oxidation or aggregate formation. Various means have been suggested by which therapeutic proteins might be modified to reduce their immunogenicity, including PEGylation, site-specific mutagenesis, exon shuffling, and humanization of monoclonal antibodies. In the future, it may even be possible to predict the immunogenicity of new therapeutic proteins more accurately, using specifically designed animal models, including nonhuman primates and transgenic mice.
CONCLUSIONS: Scientists and clinicians are becoming increasingly aware of the importance of assessing the immunogenicity of new molecules as they are introduced, and of existing molecules whenever they are modified or their manufacturing process is changed. Immune responses to therapeutic proteins are usually only of clinical significance if they are associated with the development of treatment resistance. Although various means to reduce the immunogenicity of therapeutic proteins have been suggested, monitoring for antibodies during clinical trials and postmarketing surveillance remains an important issue for all therapeutic proteins.