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Principal Investigator: Brian D. Green
Organization: GLYCOBIA, INC.
Fiscal Year: 2019
Award: $300,000
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Almost half of all men and women in the United States will be diagnosed with cancer during their lifetimes,
resulting in more than 500,000 deaths and an economic burden exceeding $200 billion annually. Cancer
immunotherapies, such as vaccines and antibodies, are emerging strategies for specifically targeting malignant
cells, while avoiding the potentially dangerous and unpleasant side effects of traditional treatments. Given that
cancer is a heterogeneous set of diseases, broadly effective immunotherapeutics would yield substantial public
health and economic benefits. Numerous cancers exhibit altered patterns of cell surface carbohydrates.
Furthermore, unlike many protein/peptide neoantigens, similar alterations occur across a diversity of
malignancies, making tumor-associated carbohydrate antigens an appealing target for immunotherapy
development. Unfortunately, carbohydrates are notoriously poor immunogens. As a consequence, despite
considerable effort towards realizing the promise of targeting differentially expressed carbohydrate antigens,
few therapies or diagnostics have been successfully developed. In those cases where glycans have been
successfully targeted, it has been the result of years of singularly focused study or serendipity rather than a
successful technological advance to be leveraged. One promising strategy to improve the immune response to
carbohydrate targets is to use bacterial outer membrane vesicles (OMVs) as carriers. OMVs, which are
composed mainly of periplasmic and outer membrane components of Gram negative bacteria, package
multiple copies of a target antigen along with immunostimulatory components in a single, easily purified unit.
Glycobia, Inc. specializes in glycoengineering Escherichia coli to produce structurally defined glycoconjugates
bearing designer carbohydrates. The central hypothesis of the proposed studies is that glycosylated OMVs
(glycOMVs) that display tumor-associated glycans will stimulate a robust immune response that can be
subsequently “glyco-focused” by boosting with the same glycans conjugated to carrier proteins not found on
OMVs. Following this heterologous immunization strategy, isolated splenocytes will be used to generate Fab-
phage display libraries to identify glycan-directed Fab antibodies that can be converted to full-length
monoclonal antibodies for use as direct immunotherapies, or as glycan-targeting sequences in next-generation
modalities such as CAR-T, bispecific antibodies, and antibody drug conjugates. The deliverables of this
proposal will be a robust method for antibody discovery that elevates and focuses the immune response to
otherwise poor immunogens. It is anticipated that this platform will be broadly applicable to the development of
engineered vaccine and antibody-based therapies targeting unique carbohydrate antigens that are differentially
expressed in human cancers.
Terms: <2-Amino-2-Deoxyglucose><2-amino-2-deoxy-D-glucose><7S Gamma Globulin><ATGN><Address><Affinity><Animals><Antibodies><Antibody Therapy><Antibody-drug conjugates><Antigen Targeting><Antigenic Determinants><Antigens><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bacterial O Antigen><Bacteriophages><Bifunctional Antibodies><Binding><Binding Determinants><Binding Proteins><Bioassay><Biologic Assays><Biological Assay><Biology><Biotech><Biotechnology><Bispecific Antibodies><Breast Cancer><CA Antigens><Cancer Patient><Cancer-Associated Carbohydrate Antigens><Cancers><Carbohydrates><Carrier Proteins><Cell surface><Cessation of life><Chemicals><Class Switching><Class Switchings><Clinical Treatment Moab><Clinical Trials><Collaborations><Dangerousness><Death><Development><Diagnosis><Diagnostic><Disease><Disialosyllactosylceramide><Disorder><Drug Targeting><E coli><E. coli><Economic Burden><Engineering><Epitopes><Escherichia coli><Exhibits><G(D3) ganglioside><GD(3)><Ganglioside GD3><Generations><Glucosamine><Glycans><Glycoconjugates><Gram-Negative Bacteria><Human><IgG><Immobilization><Immune><Immune response><Immune system><Immunes><Immunization><Immunize><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin G><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically Directed Therapy><Immunostimulation><Immunotherapeutic agent><Immunotherapy><In Vitro><Industrial Microbiology><Isotype Switching><Isotype Switchings><Lead><Length><Libraries><Ligand Binding Protein><Ligand Binding Protein Gene><MSKCC><Malignant Cell><Malignant Melanoma><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Membrane><Memorial Sloan-Kettering Cancer Center><Messenger RNA><Metabolic Glycosylation><Methods><Mice><Mice Mammals><Microarray Analysis><Microarray-Based Analysis><Modality><Modern Man><Modification><Molecular><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neuroblastoma><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><O Antigens><O-Specific Polysaccharides><Oat cell carcinoma><Oligosaccharides><Oncology Cancer><Outcome><Outcome Study><Pancreas Cancer><Pancreatic Cancer><Pattern><Pb element><Peptides><Periplasmic Space><Phage Display><Phages><Phase><Polysaccharides><Polysialic Acid><Population><Production><Prognosis><Protein Binding><Proteins><Public Health><Recombinants><Research><Rhabdomyosarcoma><Series><Small Cell Lung Cancer><Specificity><Spleen><Spleen Reticuloendothelial System><Splenocyte><Structure><System><Technology><Testing><Therapeutic><Transport Protein Gene><Transport Proteins><Transporter Protein><Tumor-Associated Carbohydrate Antigens><United States><Universities><Vaccine Design><Vaccines><Vesicle><Woman><allergic/immunologic body system><allergic/immunologic organ system><anti-cancer immunotherapy><antibody based therapies><antibody engineering><antibody treatment><antibody-based therapeutics><antibody-based treatment><anticancer immunotherapy><bacterial virus><base><bound protein><bsAb><cancer cell><cancer immunotherapy><cancer survival><cancer type><cell killing><cell transformation><clinical relevance><clinically relevant><design><designing><develop a vaccine><development of a vaccine><developmental><differential expression><differentially expressed><disialogangliosides><drug development><glycosylation><health economics><heavy metal Pb><heavy metal lead><host response><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenic><immunogenicity><immunologic preparation><immunoresponse><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><lung oat cell carcinoma><lung small cell carcinoma><lung small cell neuroendocrine carcinoma><mAbs><mRNA><malignancy><malignant breast neoplasm><malignant breast tumor><medical college><medical schools><melanoma><membrane structure><men><men's><microarray analyses><microarray technology><monosialogangliosides><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><new approaches><next generation><non-pathogenic Escherichia coli><nonpathogenic Escherichia coli><nonsmall cell lung cancer><novel><novel approaches><novel strategies><novel strategy><oat cell cancer><oncology><orthopedic freezing><outcome forecast><periplasm><periplasmic><pre-clinical study><preclinical study><programs><response><school of medicine><sialogangliosides><sialyl Lewis x><side effect><skills><small cell undifferentiated carcinoma><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptional differences><transformed cells><tumor><tumor growth><vaccine development><vaccine formulation>