Currently, there is no FDA approved therapeutic antibody capable of depleting long-lived plasma cells. A plasma cell-specific monoclonal antibody could be used to treat plasma cell malignancies (multiple myelomas), which are fatal and for which there is no effective treatment, and antibody-mediated autoimmune and severe allergic disease (e.g., systemic lupus erythematosus and asthma). Immunoglobulin (Ig)-based monoclonal antibodies that recognize plasma cell surface antigens, such as CD138 and CD38, are being evaluated for plasma cell targeting; however, these antigens are expressed by many other cell types, which complicates plasma cell targeting and creates the potential for side effects. NovAb's scientific founders discovered that primitive jawless fish, lampreys and hagfish, use highly diverse leucine-rich repeat (LRR)-based antibodies called Variable Lymphocyte Receptors (VLRs) for antigen recognition, instead of the Ig-based antibodies used by all higher vertebrates. Due to the vast evolutionary distance between humans and lampreys (~500 million years), highly conserved human proteins and carbohydrates that are "invisible" to mammalian immune systems because of self-tolerance, are likely to be immunogenic in lampreys. Capitalizing on the lack of tolerance to mammalian antigens and the unique structural features of the lamprey VLR antibodies, NovAb has developed VLR monoclonal antibodies specific for novel plasma cell-restricted antigens in humans and non-human primates. However, the plasma cell-specific VLR antibodies will need to be engineered before they can be used therapeutically. Because VLR antibodies will be seen as foreign antigens by the mammalian immune system in their native form, we propose to make "humanized" variants using human LRR receptors as scaffolds to limit immunogenicity. We will also construct VLR chimeric proteins to allow them to interface with effector mechanisms of the human immune system, such as Fc receptors and complement pathways, to facilitate the depletion of target cells.
Public Health Relevance Statement:
Public Health Relevance: The long-term goal of this project is to generate a therapeutic antibody capable of depleting malignant and pathological plasma cells. NovAb's scientific founders discovered that jawless fish, lampreys and hagfish, have an alternative type of adaptive immune system that uses Variable Lymphocyte Receptors (VLRs) composed of leucine-rich repeats for antigen recognition, instead of the immunoglobulin-based antibodies found in all jawed vertebrates. Using the lamprey immune system as a discovery tool, we have developed VLR monoclonal antibodies that are specific for plasma cells in humans and non-human primates. In the proposed studies, we will engineer the plasma cell-specific VLR antibodies to decrease immunogenicity and to interface with immune effector mechanisms in order to deplete plasma cells in vivo.
Project Terms:
Address; Adverse effects; Affinity; Allergic Disease; Antibodies; antigen binding; Antigen Receptors; Antigens; Asthma; Autoimmune Diseases; Autoimmune Process; base; Binding (Molecular Function); Binding Sites; Biological; C-terminal; Camels; Carbohydrates; Cell surface; cell type; Cells; Chimera organism; Chimeric Proteins; Cloning; complement pathway; Computer Simulation; design; design and construction; Diagnostics Research; effective therapy; Engineering; Epitopes; Evaluation; expression vector; Family; Fc Receptor; FDA approved; Fishes; Gene Conversion; gene synthesis; Geometry; Goals; Hagfish; Homologous Gene; Human; IgG Receptors; IgG1; Immune; Immune system; Immune Tolerance; Immunization; immunogenic; immunogenicity; Immunoglobulin G; Immunoglobulins; in vivo; interest; Jaw; Lampreys; Leucine-Rich Repeat; leucine-rich repeat protein; Libraries; Life; Lymphocyte; Macaca; Macaca mulatta; Malignant - descriptor; Malignant Neoplasms; Mammals; Mediating; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Multiple Myeloma; Mus; Mutagenesis; nonhuman primate; novel; Patients; Phase; Plasma Cells; polypeptide; Positioning Attribute; Protein Binding; Proteins; prototype; public health relevance; Rattus; Reagent; receptor; Receptor Gene; scaffold; Scaffolding Protein; scale up; Scientist; Self Tolerance; Shapes; Site; Specificity; Staining method; Stains; Structural Models; Structure; Surface; Surface Antigens; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic antibodies; three dimensional structure; tool; Variant; Vertebrates; Yeasts
