Subcutaneously administered anti-PD-(L)1 antibodies are predominantly absorbed via the lymphatic system, resulting in high drug exposure to draining lymph nodes.

Compared to classic intravenous (IV) administration, subcutaneous (SC) delivery of monoclonal antibodies (mAbs) offers new opportunities to improve patient compliance and healthcare efficiency. However, insufficient understanding of drug absorption process following SC administration, particularly the role of lymphatic transport, may hinder the development of SC formulations for mAbs. The current study aimed to examine the absorption route of widely used anti-PD-(L)1 mAbs following SC injection, and four marketed products (Pembrolizumab, Tislelizumab, Envafolimab, Sugemalimab) were selected as the model drugs. In the thoracic lymph duct-cannulated rat model, all mAbs were found to be primarily absorbed via the lymphatics following SC injection, with 63.1-72.0 % of the administered dose recovered in the thoracic lymph, contributing to >80 % of SC bioavailability. This absorption pattern also resulted in elevated exposure of mAbs in draining lymph nodes (an order of magnitude higher drug concentrations compared to the systemic drug exposure). In addition, markedly different lymphatic absorption profiles were observed following SC administration at different sites, reflecting specific draining routes associated with certain anatomical regions in the rat. Our data suggested that the food pad is likely the optimal SC injection site for quantitative studies of lymphatic transport, whereas injection to the lower hind leg (a common SC injection site in previous studies) appeared to underestimate the absolute extent of lymphatic drug transport in the thoracic lymph duct-cannulated rat model, as lymphatic drainage from this region partially bypasses the cannulation site, leading to incomplete collection of draining lymph.