Addressing immunogenicity and pharmacokinetic issues associated with subcutaneous administration of protein therapeutics
Fathallah, Anas Mahmoud
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The subcutaneous administration of protein therapeutics is highly desirable due to increased patient compliance and reduced healthcare cost. However, efforts to formulate protein therapeutics for sc delivery are met with major challenges. The increased immunogenicity and incomplete bioavailability after sc administration of biotherapeutics are commonly cited. The work presented in this thesis addresses both of those issues. Each chapter presented in this thesis will have its own abstract and conclusion, chapters are written in the style of the journal it was submitted to, or in the style of the journal of the American Association of Pharmaceutical Sciences (AAPS. J.). The first part of the thesis addresses the question of sc immunogenicity as compared to the iv route, followed by methods of mitigation. First, protein aggregation is examined as a contributing factor to immunogenicity following sc administration. Second, the use of adjuvants to mitigate immune response to biologics was investigated. O-Phospho-L-Serine (OPLS), a derivative of the immunomodulatory lipid phosphatidylserine, was identified as an adjuvant to mitigate protein immunogenicity. The second part of the thesis addresses the issue of incomplete bioavailability of subcutaneously administered protein therapeutics. The effects of hypertonic buffers, on lymphatic trafficking and bioavailability of protein therapeutics, were investigated using rituximab as a mAb model protein. A pharmacokinetic model was developed to describe the data and illustrate the role of hypertonicity on lymph uptake and bioavailability.