Subcutaneous Administration of Monoclonal Antibodies: Pharmacology, Delivery, Immunogenicity, and Learnings From Applications to Clinical Development.

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared to intravenous (IV) infusion through shorter administration times, made possible by convenient, patient-centric devices. A deeper understanding of clinical pharmacology principles related to efficacy and safety of SC-administered mAbs over the past decade has streamlined SC product development. This review presents learnings from key constituents of the SC mAb development pathway, including pharmacology, administration variables, immunogenicity, and delivery devices. Restricted mAb transportation through the hypodermis explains their incomplete absorption at a relatively slow rate (pharmacokinetics [PK]) and may impact mAb-cellular interactions and/or onset and magnitude of physiological responses (pharmacodynamics [PD]). Injection volumes, formulation, rate and site of injection, and needle attributes may affect PK and the occurrence/severity of adverse events like injection-site reactions or pain, with important consequences for treatment adherence. A review of immunogenicity data for numerous compounds reveals that incidence of anti-drug antibodies (ADA) is generally comparable across IV and SC routes, and complementary factors including response magnitude (ADA titer), persistence over time, and neutralizing antibody presence are needed to assess clinical impact. Finally, four case studies showcase how SC biologics have been clinically developed (1) by implementation of IV/SC bridging strategies to streamline PD-1/PD-L1 inhibitor development, (2) through co-development with IV presentations for anti-SARS CoV antibodies to support rapid deployment of both formulations, (3) as the lead route for bispecific T cell engagers (BCTEs) to mitigate BTCE-mediated cytokine release syndrome, and (4) for pediatric patients in the case of dupilumab. This article is protected by copyright. All rights reserved.