2026-09-24T13:31:14Zhttps://api.repository.cam.ac.uk/server/oai/request

oai:www.repository.cam.ac.uk:1810/3446962023-12-22T13:32:59Zcom_1810_219476com_1810_256062col_1810_219483

Engineering of an anti-PAI-1 antibody with tissue specific activation 10.17863/CAM.92119 Bleuez, Chloe Hollfelder, Florian Jermutus, Lutz 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. University of Cambridge 2021-09-30 Thesis Doctoral Doctor of Philosophy (PhD) eng Marie-Curie fellowship AstraZeneca https://www.repository.cam.ac.uk/handle/1810/344696 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/333a9634-a9fc-4138-83db-73f82699d923/download 2eb037c1517b66d67581c58327cae961 https://www.rioxx.net/licenses/all-rights-reserved/ antibody specificity kidney