Immunogenicity Of Protein Therapeutics Research Articles

Peptides identified on monocyte-derived dendritic cells: a marker for clinical immunogenicity to FVIII products

AbstractThe immunogenicity of protein therapeutics is an important safety and efficacy concern during drug development and regulation. Strategies to identify individuals and subpopulations at risk for an undesirable immune response represent an important unmet need. The major histocompatibility complex (MHC)–associated peptide proteomics (MAPPs) assay directly identifies the presence of peptides derived from a specific protein therapeutic on a donor's MHC class II (MHC-II) proteins. We applied this technique to address several questions related to the use of factor VIII (FVIII) replacement therapy in the treatment of hemophilia A (HA). Although >12 FVIII therapeutics are marketed, most fall into 3 categories: (i) human plasma-derived FVIII (pdFVIII), (ii) full-length (FL)–recombinant FVIII (rFVIII; FL-rFVIII), and (iii) B-domain–deleted rFVIII. Here, we investigated whether there are differences between the FVIII peptides found on the MHC-II proteins of the same individual when incubated with these 3 classes. Based on several observational studies and a prospective, randomized, clinical trial showing that the originally approved rFVIII products may be more immunogenic than the pdFVIII products containing von Willebrand factor (VWF) in molar excess, it has been hypothesized that the pdFVIII molecules yield/present fewer peptides (ie, potential T-cell epitopes). We have experimentally tested this hypothesis and found that dendritic cells from HA patients and healthy donors present fewer FVIII peptides when administered pdFVIII vs FL-rFVIII, despite both containing the same molar VWF excess. Our results support the hypothesis that synthesis of pdFVIII under physiological conditions could result in reduced heterogeneity and/or subtle differences in structure/conformation which, in turn, may result in reduced FVIII proteolytic processing relative to FL-rFVIII.

Maillard reaction and immunogenicity of protein therapeutics

Maillard reaction and immunogenicity of protein therapeutics

Pharmacogenetics and the Immunogenicity of Protein Therapeutics.

The recognition that genetic factors influence the heterogeneity of individual responses to medications with respect to both toxicity and efficacy is not new. However, only following dramatic advances in functional genomics during the last decade did the development of so-called personalized medicine become a realistic possibility. Although drug development approaches that integrate pharmacogenetic information about both the protein drug and its protein target appear logical, given the complexity of biological systems, the selection of appropriate biomarkers and the study design remain daunting tasks. Here we present potential applications of pharmacogenetics in the development of recombinant coagulation factors. In addition, we highlight the potential utility of a personalized approach to predicting and eventually circumventing immunogenicity using the recombinant Factor VIII in the treatment of hemophilia A as a model system. The immunogenicity of protein therapeutics is of increasing concern during the development and licensure of biologics and clearly calls for a pharmacogenetic approach. This is because, with immunogenicity, the predicament is not that all patients develop inhibitory antibodies but that some individuals, ethnicities, or other subpopulations have a stronger immunogenic reaction than others do.

Pharmacogenetics and the immunogenicity of protein therapeutics

Pharmacogenetics and the immunogenicity of protein therapeutics

Immunogenicity of protein therapeutics: The key causes, consequences and challenges

The immunogenicity of protein therapeutics has so far proven to be difficult to predict in patients, with many biologics inducing undesirable immune responses directed towards the therapeutic resulting in reduced efficacy, anaphylaxis and occasionally life threatening autoimmunity. The most common effect of administrating an immunogenic protein therapeutic is the development of a high affinity anti-therapeutic antibody response. Furthermore, it is clear from clinical studies that protein therapeutics derived from endogenous human proteins are capable of stimulating undesirable immune responses in patients, and as a consequence, the prediction and reduction of immunogenicity has been the focus of intense research. This review will outline the principle causes of the immunogenicity in protein therapeutics, and describe the development of pre-clinical models that can be used to aid in the prediction of the immunogenic potential of novel protein therapeutics prior to administration in man.

Evidence for the Presence of Glycation Adducts in Protein Therapeutics

ABSTRACTGlycation is a non-emzymatic reaction between free amino groups and reducing sugars (16), which was shown to take place also in human (13). It causes severe complications in diabetic and uremic patients, whereas in normal subjects contributes to senescence and aging. This study points to another negative aspect of glycation concerning the quality of protein therapeutics. Although therapeutic proteins are designed to be equivalent to their natural human counterparts, the development of antidrug antibodies in patients treated with proteins appears to be a rule rather than the exception (5, 21, 23). The anti-drug antibodies may sometimes cause serious complications such as allergic reactions and anaphylaxis (15). In addition, severe clinical consequences might be expected with those therapeutic proteins, whose endogenous counterparts are endowed with essential biologic functions. For example, neutralizing antibodies to megakaryocyte-derived growth factor and recombinant human erythropoietin have been found to cause severe thrombocytopenia (30) and pure red cell aplasia (14), respectively. The reasons for the immunogenicity of protein therapeutics still remain unresolved. This study provides evidence for the presence of potentially immunogenic glycation adducts in widely used protein drugs that could compromise therapeutic efficacy and patient safety.

Advances in Predicting and Manipulating the Immunogenicity of Biotherapeutics and Vaccines

Therapeutic proteins are vital to the future of human health provision and the survival and profitability of the global pharmaceutical industry. Returns from protein therapeutics are experiencing unprecedented growth: both their number and their economic dividend have increased by an order of magnitude in the last 10 years. The potential immunogenicity of protein therapeutics raises many clinical and safety concerns. Many poorly understood factors relating to both product and host affect immune responses. Available laboratory measurement of immunogenicity is of little utility for predicting the clinical properties of biotherapeutics. Coupled with assay variability and standardization issues, this precludes adequate prediction of the biological or clinical responses of therapeutic proteins, arguing for the utilization of informatic strategies in the analysis and prediction of protein immunogenicity. Currently, many unresolved issues must be addressed and thus circumvented before effective prediction can become routine.