Development of single domain antibody based-LYTACS of immune checkpoint therapeutic
Grant Data
Project Title
Development of single domain antibody based-LYTACS of immune checkpoint therapeutic
Principal Investigator
Professor Ma, Hoi Tang
(Principal Investigator (PI))
Duration
36
Start Date
2023-06-01
Amount
376806
Conference Title
Development of single domain antibody based-LYTACS of immune checkpoint therapeutic
Keywords
single domain antibody based-LYTACS, immune checkpoint therapeutic
Discipline
Pathology
HKU Project Code
PRP/049/22FX
Grant Type
Partnership Research Programme (PRP) - 2022
Funding Year
2023
Status
On-going
Objectives
Targeted protein degradation (TPD) involves the degradation of disease-related proteinsas treatment. Proteolysis-targeting-chimera (PROTAC) is the most widely studied butlimited to the intracellular protein targets. The emerging therapeutic targets, especiallyimmune-checkpoint blockers, are on the cell surface, which cannot be targeted byPROTAC. Lysosome-targeting-chimera (LYTAC), utilizes a bifunctional molecule, whereone end binds to the protein of interest (POI) and the other end recruits to a lysosometargeting receptor (LTR), enabling the targeted degradation of extracellular andcirculating proteins. Our project aims to develop the optimized system for generation ofLYTAC-based immune checkpoint blocker, which composes of the single domainantibodies (sdAb) targeting the extracellular POI and the LTR to facilitate the lysosomebased degradation.To test the therapeutic potential of our sdAb-LYTAC platform, the degradation ofextracellular targets and the circulating proteins will be tested. Notably, the high solublePD-L1 (sPDL-1) in plasma levels is believed to affect the effectiveness of the immunecheckpoint blocker. Therefore, the cell surface PDL-1 and sPD-L1 will be targeted usingin liver cancer models. The LYTAC-based immune-checkpoint blocker will represent acornerstone and are invaluable assets for the commercialization of the TPD platforms.