Proteolysis and Oxidation of Therapeutic Proteins After Intradermal or Subcutaneous Administration.

The intradermal (ID) and subcutaneous (SC) routes are commonly used for therapeutic proteins (TPs) and vaccines; however, the bioavailability of TPs is typically less than small molecule drugs given via the same routes. Proteolytic enzymes in the dermal, SC, and lymphatic tissues may be responsible for the loss of TPs. In addition, the TPs may be exposed to reactive oxygen species generated in the SC tissue and the lymphatic system in response to injection-related trauma and impurities within the formulation. The reactive oxygen species can oxidize TPs to alter their efficacy and immunogenicity potential. Mechanistic understandings of the dominant proteolysis and oxidative routes are useful in the drug discovery process, formulation development, and to assess the potential for immunogenicity and altered pharmacokinetics (PK). Furthermore, in vitro tools representing the ID or SC and lymphatic system can be used to evaluate the extent of proteolysis of the TPs after the injection and before systemic entry. The in vitro clearance data may be included in physiologically based pharmacokinetic models for improved PK predictions. In this review, we have summarized various physiological factors responsible for proteolysis and oxidation of TPs after ID and SC administration.