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Principal Investigator: Peter Fekkes
Organization: UBIQUITX, INC.
Fiscal Year: 2024
Award: $299,921
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
UbiquiTx is developing a programmable, modular therapeutic platform for the direct modification of proteins of
interest (POIs). Leveraging advances in artificial intelligence, protein engineering, and mRNA as a therapeutic
modality, this platform allows for the engineering of enzymes to precisely recognize and ‘edit’ POIs by
installing/removing post-translational modifications (PTMs). As one therapeutic application for this technology,
UbiquiTx seeks to enhance the immune targeting of diseased cells through the upregulation of selective antigen
presentation on the cell surface. T cells play a central role in immunosurveillance against viruses, other
intracellular pathogens, and cancers by recognizing short peptides presented by major histocompatibility
complex (MHC) class I molecules. These antigenic peptides are generated from proteins processed through the
ubiquitin-proteasome system, then loaded onto MHC I molecules and transported to the cell surface for
immunosurveillance. Global downregulation of antigen presentation on the cell surface is a major mechanism by
which cells escape this immune surveillance, allowing diseased cells to proliferate. Thus, overcoming MHC-I
downregulation and restoring antigen presentation represents a promising avenue for enhancing the efficacy of
and patient response to immune-based therapies.
UbiquiTx’s Chimeric Ligands for Induced Proximity (CLIPs) comprise a computationally designed guide peptide
targeting a specific POI that is fused with a protein modification enzyme component. Preliminary data has
provided compelling proof-of-concept, demonstrating the platform ability to design high-affinity peptide binders
to POIs, that swap out modification enzymes and deliver CLIPs as an mRNA therapeutic using a lipid
nanoparticle (LNP) vehicle. In this Phase I project, UbiquiTx will utilize the platform to upregulate the presentation
of disease-associated peptide antigens by MHC-I, enhancing the immune surveillance of diseased cells. CLIPs
will be designed and evaluated to promote the degradation of three key POIs: WT1, PRAME, and E7. WT1 is an
intracellular, oncogenic transcription factor present in a wide range of leukemias and solid cancers, while PRAME
is a cancer-testis antigen that provides a target for immunotherapy in acute myeloid leukemia. E7 is a human
papillomavirus (HPV)-derived protein and target for the treatment of HPV-driven cancers. Evaluating these
targets will demonstrate UbiquiTx’s platform modularity, ability to target proteins with variable expression, as well
as degrade endogenous host- and virus-derived oncogenic proteins. The proposed Specific Aims are: 1. Develop
and characterize ubiquitinase CLIPs (ubiCLIPs) for WT1, PRAME, and E7 and perform in vitro characterization
to assess target engagement and protein degradation. 2. Evaluate WT1 antigen presentation and recognition by
TCRm. UbiquiTx’s collaborator, Dr. David Scheinberg, will assess the effect of the top performing WT1 ubiCLIPs
on peptide MHC (pMHC) presentation and recognition by TCRm in relevant cell lines; also, the effects on the
immunopeptidome will be measured, with emphasis on target peptides and related proteins.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><AI system><AML - Acute Myeloid Leukemia><APF-1><ATP-Dependent Proteolysis Factor 1><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Affect><Affinity><Antigen Presentation><Antigens><Artificial Intelligence><Avidity><Basal Transcription Factor><Basal transcription factor genes><Binding><CMV><Cancers><Cell Body><Cell Line><Cell surface><Cell-Mediated Lympholytic Cells><CellLine><Cells><Cervical Cancer><Cervix Cancer><Computer Reasoning><Cytolytic T-Cell><Cytomegalovirus><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Disease><Disease Surveillance><Disorder><Down-Regulation><Engineering><Enzyme Gene><Enzymes><Future><General Transcription Factor Gene><General Transcription Factors><HCMV><HMG-20><HPV><Head and Neck Cancer><Head and Neck Carcinoma><High Mobility Protein 20><Histocompatibility Complex><Histocompatibility Complices><Human Papilloma Virus><Human Papillomavirus><Immune><Immune Surveillance><Immune Targeting><Immune mediated therapy><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunologically Directed Therapy><Immunosurveillance><Immunotherapy><In Vitro><Infection><Infectious Human Wart Virus><Kinases><Ligands><Ligase><Ligase Gene><MHC Receptor><MSKCC><Machine Intelligence><Macropain><Macroxyproteinase><Major Histocompatibility Complex><Major Histocompatibility Complex Receptor><Major Histocompatibility Complices><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Head and Neck Neoplasm><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of cervix uteri><Measures><Memorial Sloan-Kettering Cancer Center><Messenger RNA><Metabolic Protein Degradation><Methylation><Modality><Modification><Molecular Interaction><Multicatalytic Proteinase><Oncogenic><PRAME><Peptides><Phase><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Process><Proliferating><Prosome><Proteasome><Proteasome Endopeptidase Complex><Protein Engineering><Protein Modification><Protein Phosphorylation><Protein Turnover><Proteins><Proteome><Proteosome><Regulatory Protein Degradation><Research><Role><Salivary Gland Viruses><Solid><Strains Cell Lines><Synthetases><System><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Technology><Testing><Therapeutic><Therapeutic Uses><Transcription Factor Proto-Oncogene><Transcription factor genes><Transphosphorylases><Treatment Efficacy><Tumor Cell><Ubiquitilation><Ubiquitin><Ubiquitination><Ubiquitinoylation><Up-Regulation><Upregulation><Uterine Cervix Cancer><Vaccines><Validation><Viral><Virus><WAGR><WT1><WT1 Gene Product><WT1 Protein><WT1 gene><WT33><Wilms Tumor 1><Wilms tumor suppressor WT1><Work><acute granulocytic leukemia><acute myeloid leukemia><adoptive T cell transfer><adoptive T-cell therapy><cancer/testis antigen><cultured cell line><cytomegalovirus group><de-ubiquitinase><de-ubiquitinating enzyme><design><designing><genetic protein engineering><head/neck cancer><immune resistance><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immune-resistant><immuno therapy><immunogen><immunoresistance><improved><in vivo><interest><intervention efficacy><killer T cell><leukemia><lipid based nanoparticle><lipid nanoparticle><mRNA><malignancy><malignant head and neck tumor><multicatalytic endopeptidase complex><neoplasm/cancer><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><pathogen><patient response><patient specific response><preferentially expressed antigen in melanoma><prevent><preventing><programs><protein degradation><protein design><responsive patient><social role><therapeutic T-cell platform><therapeutic efficacy><therapeutic target><therapy efficacy><thymus derived lymphocyte><transcription factor><ubiquination><ubiquitin conjugation><ubiquitin isopeptidase><ubiquitin-specific isopeptidase><validations><wart virus>