Immunogenicity assessment during the development of protein therapeutics

Abstract

Objective Here we provide a critical review of the state of the art with respect to non-clinical assessments of immunogenicity for therapeutic proteins. Key findings The number of studies on immunogenicity published annually has more than doubled in the last 5 years. The science and technology, which have reached a critical mass, provide multiple of non-clinical approaches (computational, in vitro, ex vivo and animal models) to first predict and then to modify or eliminate T-cell or B-cell epitopes via de-immunization strategies. We discuss how these may be used in the context of drug development in assigning the immunogenicity risk of new and marketed therapeutic proteins. Summary Protein therapeutics represents a large share of the pharma market and provide medical interventions for some of the most complex and intractable diseases. Immunogenicity (the development of antibodies to therapeutic proteins) is an important concern for both the safety and efficacy of protein therapeutics as immune responses may neutralize the activity of life-saving and highly effective protein therapeutics and induce hypersensitivity responses including anaphylaxis. The non-clinical computational tools and experimental technologies that offer a comprehensive and increasingly accurate estimation of immunogenic potential are surveyed here. This critical review also discusses technologies which are promising but are not as yet ready for routine use.

Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

“…[1][2][3] Although mAbs possess higher target-binding specificity and are generally considered to exhibit low risk for the induction of off-target effects, mAb therapeutics may induce an unwanted immune response or immunogenicity. [4][5][6][7] Immunogenicity and the induction of anti-drug antibodies (ADAs) do not always induce adverse reactions, but they can neutralize a product's activity or change pharmacokinetics. 4 Therefore, the characterization and control of quality attributes which influence immunogenicity are both indispensable for the development of therapeutic proteins, including mAbs.…”

In silico identification and characterization of antineoplastic asparaginase enzyme from endophytic bacteria

“…The administration of therapeutic protein products to patients may be associated with eliciting antidrug antibodies . There are many experimental and protein engineering methods for assessment of the immunological properties of biological drugs and reducing the immunogenicity of biotherapeutics . However, there are some in silico methods which play significant roles in predicting unwanted immune responses .…”

“…65 There are many experimental and protein engineering methods for assessment of the immunological properties of biological drugs and reducing the immunogenicity of biotherapeutics. 66,67 However, there are some in silico methods which play significant roles in predicting unwanted immune responses. 68 According to vaxijen server prediction ( Table 4), all of the studied proteins predicted to be protective antigen except for endophytic sequences of ALU91046.1, and ALU91730.1.…”

Mitigation of T-cell dependent immunogenicity by reengineering factor VIIa analogue

“…Humoral mechanisms mediate most of the adverse effects resulting from elicitation of an immune response to a therapeutic protein product and circulating ADAs are the chief criterion for defining an immune response to therapeutic proteins. Development of ADAs can affect safety or efficacy 11,[28][29][30] may not be recognized until the commencement of large expensive phase 3 clinical studies 5 or even after approval. [31][32][33][34][35] This latestage failure of drugs adds considerable economic risk for the biotechnology industry.…”