Therapeutic proteins are playing increasingly important roles in treating numerous types of diseases. However, oral administration of proteins, especially large ones (e.g., antibodies), remains a great challenge due to their difficulties in penetrating intestinal barriers. Herein, fluorocarbon-modified chitosan (FCS) is developed for efficient oral delivery of different therapeutic proteins, in particular large ones such as immune checkpoint blockade antibodies. In our design, therapeutic proteins are mixed with FCS to form nanoparticles, lyophilized with appropriate excipients, and then filled into enteric capsules for oral administration. It has been found that FCS could promote transmucosal delivery of its cargo protein via inducing transitory rearrangement of tight junction associated proteins between intestinal epithelial cells and subsequently release free proteins into blood circulation. It is shown that at a 5-fold dose oral delivery of anti-programmed cell death protein-1 (αPD1) or its combination with anti-cytotoxic T-lymphocyte antigen 4 (αCTLA4) using this method could achieve comparable antitumor therapeutic responses to that achieved by intravenous injection of corresponding free antibodies in various types of tumor models and, more excitingly, result in significantly reduced immune-related adverse events. Our work successfully demonstrates the enhanced oral delivery of antibody drugs to achieve systemic therapeutic responses and may revolutionize the future clinical usage of protein therapeutics.
Keywords: cancer immunotherapy; immune checkpoint blockade; nanocomplex; oral delivery; therapeutic proteins; transmucosal.