Subcutaneous Administration of Antibody-drug Conjugates

Abstract Subcutaneous (SQ) delivery is emerging as a strategic alternative to intravenous (IV) dosing for antibody–drug conjugates (ADCs). The approach promises patient convenience, reduced health care costs, and potentially safer peak exposures. However, it introduces route-specific challenges including depot absorption, local tolerability, and high-concentration formulation. Early clinical and translational studies show that SQ dosing of select ADCs is feasible with predictable pharmacokinetics—typically lower Cmax and delayed Tmax, while maintaining meaningful exposure. Nevertheless, depot-site processes (e.g., protease-mediated deconjugation) can drive injection-site reactions and local toxicity unless linkers and payloads are engineered for stability in subcutaneous and lymphatic tissues. Several technology enablers are accelerating progress: (i) high-concentration, low-viscosity formulations and excipient systems that preserve stability over shelf life; (ii) recombinant human hyaluronidase co-formulations that permit larger SQ volumes and more consistent absorption; (iii) route-aware linker designs (e.g., enzymatically cleavable yet plasma-stable constructs with tuned hydrophobicity) and selection of intermediate-potency payloads can mitigate depot release while preserving systemic activity. Model-informed development, integrating PBPK with multi-analyte popPK and exposure–response, are maturing into a practical toolkit that could be used to simulate SQ absorption. Such model can also be used to forecast efficacy/safety trade-offs, and rationalize dose, interval, and formulation choices before first-in-human studies. Collectively, these advances, along with growing clinical experience in SQ administration of ADCs, are opening doors to a new generation of ADCs that can be administered with increased patient convenience and decreased health care burden. Summary SQ administration is not a simple route swap for ADCs. It involves careful consideration of chemistry, formulation, and quantitative modeling to ensure desirable clinical outcomes. Key enablers include route-conscious linker–payload choices and high-concentration developability. Hyaluronidase-enabled delivery, where appropriate, and model-guided dose selection are also important. With these in place, SQ dosing can expand access, improve patient experience, and, selectively, enhance the therapeutic window. With these elements in place, SQ ADCs are poised to transition from isolated exemplars to a reproducible development pathway.