Current and emerging strategies for subcutaneous delivery of high-concentration and high-dose antibody therapeutics.

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) offers patient-centric benefits such as self-administration, fewer hospital visits, and cost savings. However, developing high-concentration formulations (HCFs, ≥ 100 mg/mL) for SC delivery presents challenges, particularly high viscosity, which affects manufacturability and injectability. This review examines the molecular basis of viscosity in highly concentrated antibody solutions, highlighting the roles of electrostatic and hydrophobic interactions. Key formulation factors, including pH, buffers, sugars, surfactants, and ionic strength are systematically analyzed for their impact on viscosity of antibody solutions. Computational and high-throughput screening tools, including machine learning and biophysical parameters, are explored for early-stage viscosity prediction and candidate selection. Viscosity reduction strategies, including approved and emerging viscosity-reducing agents (VRA) and their synergistic combinations, are comprehensively reviewed. Alternative SC delivery approaches for high-dose antibody therapeutics, such as maximized injection volume, prefilled syringes equipped with shorter ultra-thin wall (UTW) needles or tapered needles, multiple injections per dose, wearable devices, and co-formulation with hyaluronidase, are outlined. Additionally, novel technologies like non-aqueous powder suspensions and large-volume handheld autoinjectors (AI) are discussed, though further development is needed to address usability, bioavailability, and safety concerns. By integrating computational tools, high-throughput screening, diverse viscosity reduction strategies, and alternative delivery solutions, this review provides a structured framework for overcoming high-viscosity and high-dose challenges, facilitating the development of patient-friendly antibody therapeutics for SC administration.