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, preclinical screening methods, and strategies to mitigate immunogenicity.

Keywords: antibody(s); immune response(s); immunogenicity; immunology; pharmacodynamics; pharmacokinetics; protein(s).

Figure 1:

Antibody Dependent Cellular Cytotoxicity Mechanism: When Mabs bind to target antigen on the cell surface, it can lead to natural killer cells binding to the Fc region via CD16. Activation of this receptor leads to secretion of cytotoxic granules that enter the healthy cell, forcing it to undergo apoptosis.

Figure 2:

Complement Dependent Cytotoxicity: When Mabs bind to target antigen, it can deposit in healthy tissue. Circulating complement can bind to the immune complex and trigger complement activation, leading to cell death.

Figure 3:

A Two compartment model (1) depicting the impact of ADA on the PK of a protein. Protein is administered into the central compartment (C1) where it can distribute into the tissue compartment (C2). CL₁ and CL₂ depict clearance from the central compartment and tissue compartment, respectively. The left side depicts immune complex formation. ADA in the central compartment (ADA) can bind to protein to form immune complexes (ADA+P) that can be directly eliminated via degradation pathways (CL₃), complementing CL₁ and CL₂. The second model (2) has the same basic structure, with the addition of T_lag component (ADAL), accounting for the time it takes to initiate an immune response. ADA begins as hypothetical bolus dose before passing through a series of compartments before reaching the central compartment.

Figure 4:

Effect of various immunomodulatory drugs on the immune system. Rapamycin inhibits T and B cell activation through the mTOR pathway. Rituximab blocks CD20, killing CD20 expressing B cells. Methotrexate inhibits DNA synthesis and kills rapidly dividing cells. Bortezomib inhibits proteasomes, promoting apoptosis in rapidly dividing cells.