Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy

Abstract

The development of therapeutic proteins requires the understanding of the relationship between the dose, exposure, efficacy, and toxicity of these molecules. Several intrinsic and extrinsic factors contribute to the challenges for measuring therapeutic proteins in a precise and accurate manner. In addition, induction of an immune response to therapeutic protein results in additional complexities in the analysis of the pharmacokinetic profile, toxicity, safety, and efficacy of this class of molecules. Assessment of immunogenicity of therapeutic proteins is a required aspect of regulatory filings for a licensing application and for the safe and efficacious use of these compounds. A systematic strategy and well-defined criteria for measuring anti-drug antibodies (ADA) have been established, to a large extent, through coordinated efforts. These recommendations are based on risk assessment and include the determination of ADA content (concentration/titer), affinity, immunoglobulin isotype/subtype, and neutralization capacity. This manuscript reviews the requirements necessary for understanding the nature of an ADA response in order to discern the impact of immunogenicity on pharmacokinetics/pharmacodynamics and efficacy.

Fig. 1

Example of multiple clearance pathways affecting the pharmacokinetics of a typical protein therapeutic. Depicted is a two-compartment pharmacokinetic model with intravenous administration of a dose (D), concentrations of the protein therapeutic in the central (PT ₁) and peripheral (PT ₂) compartment, and interdepartmental clearance Q. The pharmacokinetic model includes two clearance pathways, one from the central compartment (CL ₁) representative of for example renal metabolism or proteolytic degradation through the reticuloendothelial system, and a second unspecific proteolytic degradation pathway from the peripheral compartment (CL ₂) Added to these two clearance pathways is, on the right side, a target-mediated disposition pathway that constitutes interaction of the protein therapeutic with its pharmacologic target receptor, which is in a homeostatic equilibrium of synthesis and degradation (synthesis rate k _syn and degradation rate constant k _deg). The dynamic equilibrium for the formation of the resulting protein therapeutic–receptor complex (PT–R) is determined through the association rate constant k _on and the dissociation rate constant k _off. The formation of PT–R does not only elicit the pharmacologic effect, but also triggers degradation of the complex. Thus, target binding and subsequent PT–R degradation constitute an additional clearance pathway for the protein therapeutic (CL ₃). The left side of the graphic depicts the effect of an immune response to the protein therapeutic resulting in ADA formation. Again, the circulating concentration of the ADA is determined by a homeostatic equilibrium between its formation rate (k _formation) and a catabolic turnover process (rate constant k _cat). The ADA response results in the formation of immune complexes with the drug (ADA–PT). Dependent on the size and structure of the immune complexes, endogenous elimination pathways through the reticuloendothelial system may be triggered, most likely via Fcγ-mediated endocytosis. Thus, immune complex formation and subsequent degradation may constitute an additional clearance pathway (CL ₄) for protein therapeutics