Wednesday, May 8, 2024
5/8/2024
Abstract Targeted protein degradation by chimeric molecules has emerged as a novel therapeutic modality. The bifunctional chimeric molecules usually have one end binding to the protein of interest (POI) and the other end directing the ternary complex towards the degradation in proteasome or lysosome. The PROteolysis TArgeting Chimera (PROTAC) received the most attention to date. PROTACs contain an E3 ubiquitin ligase ligand to direct the POI for ubiquitination and route it to the proteasome for degradation. Because of this, PROTACs are only capable of depleting intracellular proteins. About 40% of the proteome are extracellular secreted and membrane proteins and many of them are related to cancers. To broaden the scope of targets to include extracellular proteins, the LYsosome TArgeting Chimeras (LYTAC) were recently reported by us and others. LYTACs are created by conjugating a ligand of a lysosome targeting receptor (LTR) on the cell surface with a ligand that can bind to the extracellular POI. The first two LTRs employed for LYTACs are lectins or carbohydrate binding proteins: cation-independent mannose 6-phosphate receptor (CIM6PR) and asialoglycoprotein receptor (ASGPR). The receptor-ligand interaction triggers the internalization of the extracellular proteins through receptor-mediated endocytosis, further inducing the degradation of the targets in the lysosome. However, CIM6PR is ubiquitously expressed in most types of cells, while ASGPR is mainly expressed on liver. It would be ideal to recruit a LTR that is overexpressed on cancer cells to degrade extracellular POIs associated with cancers to achieve high efficiency and selectivity. After examining a series of cell surface receptors that are overexpressed on cancers, we found that chimeric molecules that recruit folate receptor (FR) could degrade extracellular POIs on cancer cells highly effectively. In this application, we will demonstrate for the first time that the conjugation of FR ligand, folate (FA), to binders of POI on the membrane of cancer cells can create degraders that are capable of selectively degrading the endogenous membrane POI on cancers. We propose to exploit the potential of this strategy to develop novel FA-antibody conjugates that can degrade check point inhibitors, such as programmed death ligand 1 (PD-L1), for the treatment of various cancers with a focus on head neck cancers (HNC). In Aim 1, we will synthesize various FA-antibody conjugates and test their degradation activity in cells. In Aim 2, we will evaluate the in-vivo degradation activity and anti-tumor efficacy of the PD-L1 degrader in syngeneic and humanized mouse models with a focus on HNC. In Aim 3, we propose to study the mechanism of the FR-mediated degradation of PD-L1 and the underlying principle for improved anti-tumor efficacy. These studies will facilitate the establishment of a general platform for the development of efficient and tissue-selective degraders for cancer associated extracellular POIs, which will lead to effective therapeutics for the treatment of many types of cancers.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
