Immunogenicity of biologics delivered in the subcutaneous space: Delineating the contributing factors

The subcutaneous (SC) route of administration for therapeutic proteins (TPs) offers advantages such as patient convenience, reduced delivery complexity, and self-administration leading to enhanced adherence. Although SC delivery may be perceived to have higher immunogenicity risk than intravenous (IV) administration due to longer antigen exposure and proximity to resident professional immune cells, recent data suggest that immunogenicity rates of TPs are comparable between SC and IV administration routes. Factors thought to contribute to immunogenicity risk encompass dosing regimen (route of administration), and patient and product-related elements. Product related factors include liabilities related to protein sequence, critical quality attributes that may occur during process development and manufacturing such as post-translational modifications, propensity to aggregate, presence of impurities, and the drug's mechanism of action. Advances in formulation, delivery systems, molecular design and associated biophysical characterization can help mitigate some of these risks. The Immunogenicity Sub team of the Subcutaneous Drug Development & Delivery Consortium, held a workshop at the 2023 PEGS Boston meeting, focused on delineating the immunogenicity risk factors carried by SC administration. In this paper, the team presents the outcome of the workshop and discusses the most recent clinical examples of SC administration which highlight that the SC route is not inherently more immunogenic than IV administration and requires context-specific evaluation. Additionally, the paper provides an overview of the current landscape in non-clinical immunogenicity risk assessment focused on novel in vivo and in vitro models, together with identified gaps and opportunities for further improvement of immunogenicity prediction as it relates to SC route.