Subcutaneous Administration of Antibody–Drug Conjugates: Current Challenges, Emerging Opportunities, and Future Perspectives

Abstract Antibody–drug conjugates (ADCs) are a rapidly growing class of targeted therapeutics designed to deliver potent payloads while minimizing systemic toxicity. Despite significant progress, all approved ADCs are administered intravenously (IV). In contrast, subcutaneous (SC) delivery is well established for antibodies, offering shorter administration time, improved convenience, and the potential for outpatient or home-based treatment. Extending SC delivery to ADCs is therefore attractive but introduces unique challenges related to structural complexity, linker–payload instability, and cytotoxic payloads. This review evaluates the feasibility of SC ADCs by integrating insights from pharmacokinetic and pharmacodynamic studies, emerging clinical data, and advances in molecular design, formulation, and delivery technologies. Key challenges include limited clinical comparisons between IV and SC routes, uncertain bioavailability and tumor exposure, linker–payload instability, injection-site reactions, and high-concentration formulation constraints. Enabling strategies, such as rational molecular design, hyaluronidase-enabled delivery, polymer-based systems, and conversion of IV ADCs to SC dosing, are discussed. Recent advances, exemplified by JSKN033, demonstrate the feasibility of high-concentration liquid co-formulation approaches for SC administration and may represent a future direction. Evidence across oncology and non-oncology programs suggests that while SC delivery is achievable, success is highly molecule dependent. Overall, transitioning ADCs from IV to SC requires case-by-case evaluation and coordinated innovation across rational molecular design, formulation, and nonclinical and clinical development to realize the full patient-centric benefits of this approach.