Cancer immunotherapeutic bi-specific proteins and engineered Chimeric Antigen Receptor T cells (CAR T) have shown remarkable clinical activity, with complete response rates as high as ~90% for B cell malignancies. However, applying these two therapeutic approaches to the vast majority of cancer types is restricted by multiple factors. First, there are only a small number of known cell-surface proteins that are sufficiently specific to cancer to safely allow targeting by antibodies. This is particularly true for solid cancers, where unlike hematopoietic malignancies; loss of healthy cells cannot be readily replenished by stem cell progenitors. Second, as each individual bi-specific protein and/or CAR T cell only target a single cancer type, different bi-specific and/or CAR T cells will need to be developed for each cancer type. This greatly increases development time and costs. Third, neither therapy is able to effectively target the most abundant and widely expressed cell surface cancer antigens known, namely Tumor associated carbohydrate antigens (TACAs). Many cancer specific antigens are not proteins, but rather complex carbohydrates that have limited or no expression in normal tissues. Indeed, altered glycosylation is a near universal feature of cancer. While TACAs have been known for decades, generation of effective monoclonal antibodies specific to complex carbohydrates has proven to be very challenging, greatly limiting their usefulness as targets for cancer immunotherapy. Here we propose to address these issues and develop a novel class of immunotherapeutics that target the Tn antigen, an abnormal O-linked carbohydrate common on many solid and hematopoietic cancers but not present on normal tissue. We have termed this technology as Glycan-dependent T cell Recruiter (GlyTR, pronounced glitter). We have generated and optimized a GlyTR bi-specific protein that 1) specifically binds to both Tn antigen and CD3, 2) activated T cells in the presence but not absence of Tn+ cancer cells and 3) induced T cell dependent killing of diverse solid and liquid cancer cells in vitro and in vivo. However, serum half-life was ~2 hrs, which is similar to the FDA approved bi-specific protein Blincyto that requires continuous intravenous infusion (via a pump) over 28-days (first 9 days in hospital). To avoid this cumbersome treatment regimen for GlyTR, here we propose to extend the half-life by adding a human-serum albumin (HSA) domain. The half-life of HSA is ~3 weeks and has been successfully fused to therapeutic proteins to markedly increase half-life, including two FDA approved therapeutics. Here we propose to genetically fuse HSA to GlyTR (HSA-GlyTR) and confirm binding to Tn antigen, cancer-killing activity and improved half-life. Specifically, we propose the following two Aims. Aim 1 optimizes the HSA-GlyTR bi-specific protein for activity and drug development. Aim 2 explores the efficacy and safety of the optimized HSA-GlyTR bi-specific protein. If successful, these experiments will allow subsequent IND enabling studies to develop an entire new class of cancer killing immunotherapeutics uniquely capable of targeting multiple solid and hematopoietic cancers with a single therapeutic.
Public Health Relevance Statement: Project Narrative Directing the immune system to kill cancer cells is a highly potent way of treating cancer. Abnormal addition of carbohydrates to proteins is a near universal feature of cancer, however current immunotherapies cannot readily target these. Here we examine the possibility of a novel technology that directs immune cells to kill cancer cells based on expression of altered carbohydrates.
Project Terms: Antibodies ; Monoclonal Antibodies ; Clinical Treatment Moab ; mAbs ; Antigens ; immunogen ; Tumor-Associated Carbohydrate Antigens ; CA Antigens ; Cancer-Associated Carbohydrate Antigens ; Bite ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Carbohydrates ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Engineering ; Galactose ; D-Galactose ; Galactopyranose ; Galactopyranoside ; glycosylation ; Metabolic Glycosylation ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Half-Life ; Hospitals ; Human ; Modern Man ; Human Activities ; Immune system ; allergic/immunologic body system ; allergic/immunologic organ system ; Immunotherapy ; Immune mediated therapy ; Immunologically Directed Therapy ; immune therapeutic approach ; immune therapeutic interventions ; immune therapeutic regimens ; immune therapeutic strategy ; immune therapy ; immune-based therapies ; immune-based treatments ; immuno therapy ; In Vitro ; Lectin ; Liver ; hepatic body system ; hepatic organ system ; Lymphocyte ; Lymphatic cell ; Lymphocytic ; lymph cell ; macrophage ; MÏ ; Mus ; Mice ; Mice Mammals ; Murine ; Parents ; Polysaccharides ; Glycans ; Protein Engineering ; genetic protein engineering ; protein design ; Proteins ; Risk ; Safety ; Sensitivity and Specificity ; Serum Albumin ; stem cells ; Progenitor Cells ; T-Lymphocyte ; T-Cells ; thymus derived lymphocyte ; Technology ; Time ; Treatment Protocols ; Treatment Regimen ; Treatment Schedule ; Tumor Antigens ; Tumor-Associated Antigen ; cancer antigens ; tumor-specific antigen ; Tn antigen ; Generations ; Mediating ; CD3 Antigens ; CD3 ; CD3 Complex ; CD3 molecule ; OKT3 antigen ; T3 Antigens ; T3 Complex ; T3 molecule ; base ; Pump ; improved ; Solid ; Clinical ; Link ; Blood group antigen S ; S antigen ; Serum ; Blood Serum ; Individual ; nonhuman primate ; non-human primate ; sugar ; Binding Proteins ; Ligand Binding Protein ; Ligand Binding Protein Gene ; Protein Binding ; bound protein ; Cell Surface Proteins ; cancer immunotherapy ; anti-cancer immunotherapy ; anticancer immunotherapy ; immune-based cancer therapies ; immunotherapy for cancer ; immunotherapy of cancer ; Recycling ; Therapeutic ; fluid ; liquid ; Liquid substance ; Normal Tissue ; Normal tissue morphology ; Malignant Cell ; cancer cell ; Hematopoietic Cell Tumor ; Hematopoietic Malignancies ; Hematopoietic Neoplasms including Lymphomas ; Hematopoietic Tumor ; Hematopoietic and Lymphoid Cell Neoplasm ; Hematopoietic and Lymphoid Neoplasms ; Malignant Hematopoietic Neoplasm ; blood cancer ; Hematopoietic Neoplasms ; Hematologic Cancer ; Hematologic Malignancies ; Hematological Malignancies ; Hematological Neoplasms ; Hematological Tumor ; Hematopoietic Cancer ; Malignant Hematologic Neoplasm ; Hematologic Neoplasms ; FcRn ; FcRn neonatal transfer protein ; neonatal Fc receptor ; Immunes ; Immune ; Complex ; Treatment Period ; treatment days ; treatment duration ; Location ; Heterograft ; Heterologous Transplantation ; Xenograft ; Xenotransplantation ; xeno-transplant ; xeno-transplantation ; Xenograft procedure ; meetings ; Toxicities ; Toxic effect ; complete response ; In complete remission ; novel ; novel technologies ; new technology ; Cell surface ; drug development ; native protein drug ; pharmaceutical protein ; protein drug agent ; therapeutic protein ; immune drugs ; immune-based therapeutics ; immunologic preparation ; immunologic therapeutics ; immunotherapeutics ; immunotherapy agent ; Immunotherapeutic agent ; Molecular Interaction ; Binding ; Address ; Continuous Intravenous Infusion ; in vivo ; Development ; developmental ; cost ; B lymphoid malignancy ; B cell malignancy ; cancer type ; FDA approved ; in vitro activity ; clinical candidate ; experimental study ; experiment ; experimental research ; preclinical development ; pre-clinical development ; bi-specific T cell engager ; bispecific T cell engager ; chimeric antigen receptor T cells ; CAR T cells ; T cells for CAR ; chimeric antigen receptor (CAR) T cells ; pharmacokinetics and pharmacodynamics ; PK/PD ; cancer immunotherapeutics ; cancer immune therapeutics ;
