Engineering the subcutaneous delivery of antibody-drug conjugates.

Fiche publication

Date publication

avril 2026

Journal

Journal of controlled release : official journal of the Controlled Release Society

Auteurs

Membres identifiés du Cancéropôle Est :
Pr PIVOT Xavier , Dr DETAPPE Alexandre

Tous les auteurs :
Detappe A, Gutiérrez-Blanco M, Pivot X

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/42002047

Résumé

Subcutaneous (SC) delivery has evolved beyond a convenience formulation to become an operational re-architecture of cancer care, with the potential to convert infusion-centered oncology into a distributed model without compromising exposure, safety, or product quality. Monoclonal antibodies have already completed this transition, establishing that the SC route delivers clinical equivalence while improving patient experience and system efficiency. Antibody-drug conjugates (ADCs) represent the next frontier, yet they remain almost exclusively intravenous (IV). This gap reflects not an incompatibility with SC delivery but rather the specific points at which ADCs stress the delivery stack: tissue poroelasticity and backpressure, extreme concentration requirements, non-Newtonian injectability, route-dependent linker degradation, and payload-driven interfacial instability. Here we argue that these barriers are tractable design targets amenable to advanced materials and integrated engineering. In this perspective, we outline the conceptual and technical approaches required to enable subcutaneous ADC delivery. We frame the SC compartment as a biophysical reactor governed by interstitial osmotic pressure, convection-dominated transport, and immune surveillance. We then outline two enabling pillars already in motion, namely transient matrix modulation (for example, hyaluronidase-mediated hyaluronic acid depolymerisation) and high-concentration formulation science (>100 mg mL), and show why ADCs require a fundamentally different playbook than antibodies alone. Finally, we position injectable, biodegradable, stimulus-responsive polymers and hydrogels as the enabling layer that can co-control injectability, depot protection, linker integrity, and release kinetics under SC constraints (pH ∼6.8, volume-limited compliance). SC ADC formulations are inevitable because they align clinical need, patient preference, and healthcare capacity. However, we propose that the systems most likely to succeed will be those that co-design molecule, formulation, material, process, and device as a single integrated platform.