Immunogenicity of Protein Pharmaceuticals

Abstract

Protein therapeutics have drastically changed the landscape of treatment for many diseases by providing a regimen that is highly specific and lacks many off target toxicities. The clinical utility of many therapeutic proteins has been undermined by the potential development of unwanted immune responses against the protein, limiting their efficacy and negatively impacting its safety profile. This review attempts to provide an overview of immunogenicity of therapeutic proteins, including immune mechanisms and factors influencing immunogenicity, impact of immunogenicity, pre-clinical screening methods, and strategies to mitigate immunogenicity.

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.…”

Critical Issues in the Development of Immunotoxins for Anticancer Therapy

“…74 Nevertheless, some mutations introduced to eliminate B-cell epitopes created new T-cell epitopes, 74 thus revealing the difficulty with complete deimmunization of protein-based therapeutics, including ITs. 86 Of note, deimmunizing substitutions in PE24 intended to remove the T-cell epitope actually reduced immunogenicity by perturbing antigen processing. 87 Among the deimmunized ITs, LMB-100 (B-cell epitopeemutated PE24 fused with anti-CD22 Fab) 88 is now in clinical trials (Table 1).…”

“…89 Clinical trials of the various deimmunized ITs with better results are anticipated (Table 1). 71,90 Aside from the heterologous toxin moiety, the antibody-based targeting moiety could be immunogenic, 86 especially a moiety based on murine and chimeric antibodies used in the firstand second-generation ITs. 72 To address this problem, humanized and fully human antibodies are utilized in a recent version of ITs.…”

The Emerging Jamboree of Transformative Therapies for Autoimmune Diseases

“…In addition to the specific target effects, therapeutic proteins, particularly when they contain non-human sequences and/or are repeatedly administered, can be immunogenic and promote host anti-drug antibody (ADA) responses. The clinical utility of immunotherapeutics may be impacted by these ADA, since they could neutralize the therapeutic effects of the medicine and/or induce hypersensitivity reactions in the treated patient (290,291). Strategies to mitigate these risks included switching to a different molecule with similar targeting capabilities, engineering the product to eliminate as much as possible the non-human sequences (i.e., mouse antibody framework), reducing the chance to generate protein aggregates, eliminating Fc receptor binding ability or inducing immune tolerance.…”