High-dose biologics and bioconjugates delivery: Integrating molecular optimization with device design and routes of...

In recent years, biologics-based modalities have increased significantly across various therapeutic areas. Monoclonal antibodies (mAbs) and emerging bioconjugates such as antibody-drug conjugates (ADCs) and antibody-oligonucleotide conjugate (AOCs) now span oncology and immunology areas. This growth has made delivery method and route of administration central to the drug product design. From a patient perspective there is a need for improved treatment accessibility and convenience. This need has driven a transition from intravenous (IV) infusion to subcutaneous (SC) delivery. The shift has accelerated the development and approval of biologic-device combination products, such as prefilled syringes, autoinjectors, and on-body delivery systems (OBDS) for SC administration of mAbs. Despite these advances, SC delivery is associated with pharmacokinetic and formulation challenges. These challenges are intrinsic to the molecule and can affect the dose delivery and frequency of administration. Short half-life, suboptimal bioavailability, and target-mediated drug disposition (TMDD) represent typical pharmacokinetic failure modes. Additionally, SC administration of large volumes (> 2 mL) and/or high concentrations (≥ 150 mg/mL) presents challenges, such as viscosity limitations, injection site reactions (ISRs), and injection related pain. For bioconjugates, the payload chemistry, linker stability, and drug-to-antibody ratio introduces further considerations that influence the route of administration. Together, these constraints define the boundaries within which SC delivery strategies must operate. Numerous strategies are currently being developed to address these challenges. At the molecular level, Fc engineering approaches such as YTE and LS mutations extend the half-life of antibodies and aim at reducing dosing frequency. On the other hand, enzyme-assisted delivery using recombinant hyaluronidase facilitates large volume SC administration by transiently increasing tissue permeability. At a formulation level, strategies such as viscosity-reducing excipients, computational modeling, and high throughput screening are increasingly employed to enable high-concentration drug products. On the device side, large volume autoinjectors and on-body delivery systems (OBDS) are being developed to break through 1-2 mL volume limitations with existing devices. This enables self-administration of higher volume drug products which was previously restricted to health care settings. In parallel, complementary delivery routes such as intradermal (ID) via hollow microneedles are being explored. ID delivery due to its proximity to dermal lymphatic offers potential uptake of drugs thereby improving pharmacokinetics. Additionally, due to its minimally invasive nature, this route of administration has the potential to address injection pain related issues. Collectively, convergence of routes of administration (SC or ID) with advancements in molecular engineering, formulation science, and device technology is essential for improved drug delivery. Emerging modalities will further continue to influence the development of devices, including considerations for dosing frequency. Achieving this integrated vision requires a deeper understanding of pharmacokinetic failure modes and regulatory frameworks governing biologic-device development combination products.