Antibody-based therapies can have shortcomings if on-target activity causes dose-limiting toxicities. A pro-antibody, inspired by naturally occurring, proteolytically activated pro-forms of endogenous proteins, is an antibody variant which remains masked for antigen binding until activated locally by an organ-selective protease. This approach is useful to redirect the activity of an antibody recognising a widely distributed target to the site of the underlying pathology of the disease. Pro-antibodies have been described for targeting the tumour microenvironment which has a very specific protease expression signature. My aim is to investigate the use of pro-antibodies for tissue targeting. By using anti-PAI-1 pro-antibodies to specifically target the kidney for the treatment of chronic kidney disease to minimise observed cardiotoxicities, my work aims to validate this technique as a POC. To this end, I have designed a pro-antibody, based on the PAI-1 antibody MEDI-579. Two different types of masking domains are described, peptides and DARPins, which I selected against the MEDI-579 paratope. Using human and rodent transcriptomics data, three proteases, renin, hepsin and MMP-7, were identified that appear restricted to the kidney and have a specific cleavage signature. Activation of the pro-antibody with the renin protease has been demonstrated in vitro and ex vivo and work is on-going to demonstrate the activation in vivo and to characterise the properties of the anti-PAI-1 pro-antibody.