<p>Subcutaneous (SC) administration of therapeutic antibodies offers advantages over intravenous (IV) delivery, including improved patient convenience and a pharmacokinetic (PK) profile characterized by lower peak plasma concentrations without affecting overall exposure. These benefits may extend to antibody–drug conjugates (ADCs), but development has been limited by concerns that cytotoxic payloads could persist at the SC injection site, causing local tissue toxicity. This study evaluated the local tolerability and PK of SC administration of two marketed ADCs containing camptothecin payloads—sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-Dxd)—in miniature pigs, with and without recombinant human hyaluronidase PH20 (rHuPH20), an enzyme that facilitates rapid dispersion and absorption. Across injection volumes of 1–20 mL, rHuPH20 improved injection performance, reduced swelling and back-leakage and resulted in an absence of adverse histologic changes. SC delivery with rHuPH20 increased systemic exposure (AUC) of total ADC and payload by 33–54% compared to SC without rHuPH20, reaching 52–80% of the IV AUC while maintaining substantially lower C_max values (25–39% of IV). In skin tissue, rHuPH20 reduced local retention of ADC components by 41–87%, indicating enhanced dispersion and accelerated absorption. These findings demonstrate that rHuPH20 enables safe and efficient SC delivery of ADCs in an animal model that closely reflects human SC tissue architecture and lymphatic drainage, improving systemic bioavailability and local tolerability. The resulting PK profile may mitigate C_max-driven ADC toxicities and optimize dosing of ADCs with narrow therapeutic windows.</p> Graphical Abstract <p></p>