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Principal Investigator: Weiping Tang
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $394,661
Funding agency: National Cancer Institute
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.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><APF-1><ASGP-R><ATP-Dependent Proteolysis Factor 1><Adaptive Immune System><Address><Antibodies><Asialoglycoprotein Receptor><Asialoorosomucoid Receptor><Asialoorosomucoid-Binding Protein><Attention><Autophagocytosis><B7-H1><B7H1><Binding><Body Tissues><CD274><CIMPR><Cancer Treatment><Cancers><Carbohydrate Chemistry><Cell Body><Cell Surface Receptors><Cell membrane><Cell secretion><Cell surface><Cells><Cellular Membrane><Cellular Secretion><Checkpoint inhibitor><Chimera><Chimera organism><Complex><Cysteine><Cytoplasmic Membrane><DNA Molecular Biology><Data><Degradation Pathway><Degradative Pathway><Development><E3 Ligase><E3 Ubiquitin Ligase><Endocytosis><Engineering><Environment><Evaluation><Experimental Designs><Extracellular Protein><Folate><Folic Acid><Foundations><Glycans><HMG-20><Half-Cystine><Head and Neck><Head and Neck Cancer><Head and Neck Carcinoma><Head and neck structure><High Mobility Protein 20><Human><IGF2R><IGF2R gene><Immune checkpoint inhibitor><Immune mediated therapy><Immunologically Directed Therapy><Immunotherapy><In Vitro><Insulin-Like Growth Factor 2 Receptor><Investigation><L-Cysteine><L-Lysine><Lectin><Ligand Binding><Ligands><Link><Liver><Lysine><Lysosomes><MPRI><Macropain><Macroxyproteinase><Malignant Cell><Malignant Head and Neck Neoplasm><Malignant Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mannose 6-Phosphate Receptor, Cation-Independent><Mediating><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic Protein Degradation><Mice><Mice Mammals><Modality><Modern Man><Molecular Biology><Molecular Interaction><Multicatalytic Proteinase><Murine><Mus><Neck Cancer><Normal Tissue><Normal tissue morphology><Organelles><PD-L1><PDL-1><PDL1><PDX model><Patient derived xenograft><Plasma Membrane><Play><Polysaccharides><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Prosome><Protac><Proteasome><Proteasome Endopeptidase Complex><Protein Turnover><Proteins><Proteolysis targeting chimeric><Proteome><Proteosome><Pteroylglutamic Acid><Receptor Protein><Recycling><Regulatory Protein Degradation><Reporting><Role><Route><Series><Standardization><Structure><Surface Proteins><System><Techniques><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Ubiquitilation><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Vitamin M><acquired immune system><anti-cancer immunotherapy><anti-cancer therapy><antibody assay><antibody based test><antibody conjugate><antibody test><anticancer immunotherapy><autophagy><cancer cell><cancer immunotherapy><cancer therapy><cancer type><cancer-directed therapy><carbohydrate binding protein><carbohydrate receptor><cartilage link protein><cell type><chimeras><design><designing><developmental><experience><experiment><experimental research><experimental study><experiments><extracellular><folate carrier><folate receptor><folate-binding protein><folate-methotrexate transporter><folic acid binding protein><folic acid receptor><head/neck cancer><hepatic body system><hepatic organ system><human disease><humanized mice><humanized mouse><immune check point inhibitor><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><inhibitor><innovate><innovation><innovative><interest><link protein><malignancy><malignant head and neck tumor><malignant neck tumor><membrane structure><methotrexate-binding protein><mouse model><multicatalytic endopeptidase complex><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><overexpress><overexpression><patient derived xenograft model><plasmalemma><programmed cell death ligand 1><programmed cell death protein ligand 1><protein bound carbohydrate><protein death-ligand 1><protein degradation><protein homeostasis><proteolysis targeting chimera><proteostasis><public health relevance><receptor><receptor mediated endocytosis><recruit><social role><therapeutically effective><tumor><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase><vitamin Bc>