SBIR-STTR Award

The overall goal of this project is to develop a novel therapeutic for the treatment of pemphigus. Pemphigus involves blistering of the skin or mucosal surfaces and can lead to difficulty in swallowing, very painful lesions, and a ~2-3 fold increased risk of mortality. About 90-95% of pemphigus cases can be accounted for by pemphigus vulgaris (PV) or pemphigus foliaceus (PF). Autoantibodies of the IgG class that are specific for desmogleins 1 and 3 (Dsg1 and Dsg3) disrupt the desmosomal-mediated adhesion of keratinocytes and are the causative agents of disease. PV can present as a mucosal-dominant form involving Dsg3-specific autoantibodies, or a form with both Dsg1- and Dsg3-specific autoantibodies that affects skin and mucosal surfaces. PF is a skin-dominant disease, involving only Dsg1-specific autoantibodies. Current treatments for pemphigus, such as the combination of corticosteroids and the B cell- depleting antibody, rituximab, have associated adverse effects such as osteoporosis and hypertension. In addition, the onset of action of rituximab takes several months since this therapeutic agent targets B cells, rather than the autoantibodies themselves. The combination of rituximab with tapered corticosteroids is also accompanied by a significant relapse rate (25-60%) and increased infection risk due to the immunosuppressive effects of B cell depletion. Other therapeutic approaches for pemphigus include the use of intravenous gammaglobulin, plasmapheresis or immunoadsorption, and can lead to undesirable side effects. Consequently, there is an unmet need to develop therapies for pemphigus that have rapid onset and high specificity for the autoantibodies. This application seeks to address the need for new and improved therapies for pemphigus by generating engineered, antibody-based reagents that specifically and rapidly deplete Dsg-specific antibodies. Importantly, these depleting agents are highly selective and do not affect the levels of other antibodies that have a protective role against infection. This first-in-class, novel technology has been named Seldeg technology (for selective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target Dsg-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. The proposed approach could be transformative for the management of pemphigus, and also has relevance to the use of Seldeg-based strategies for multiple other clinical settings where pathogenic antibodies cause disease.

Public Health Relevance Statement:
PROJECT NARRATIVE Treatments that are currently available for antibody-mediated diseases such as the autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are generally immunosuppressive, are associated with adverse events and/or have limited efficacy. To address these issues, in this application we propose to develop a novel treatment that selectively removes the autoreactive antibodies which are involved in the disease process, without affecting the levels of other antibodies that are important for protection against infectious agents such as bacteria and viruses. This approach has the potential to be a game-changer for the clinical management of PV and PF.

Project Terms:
acantholytic; Acantholysis; Adhesions; Corticoids; Corticosteroids; Adrenal Cortex Hormones; 21+ years old; Adult Human; adulthood; Adult; Affect; After Care; After-Treatment; post treatment; Aftercare; Antibodies; immunogen; Antigens; Autoantibodies; autoimmune antibody; autoreactive antibody; self reactive antibody; Autoimmune Diseases; autoimmune condition; autoimmune disorder; autoimmunity disease; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Bacteria; Biological Assay; Assay; Bioassay; Biologic Assays; Bulla; Bleb; Blister; Bullous Lesion; Vesication; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; Deglutition; Swallowing; Desmosomes; Macula Adherens; Node of Bizzozero; Spot Desmosome; Disadvantaged; Disease; Disorder; Engineering; Gamma globulin; γ globulin; Goals; Hypertension; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; high blood pressure; hyperpiesia; hyperpiesis; hypertensive disease; hypertensive disorder; Immunoglobulin G; 7S Gamma Globulin; IgG; Immune Tolerance; Immunologic Tolerance; immune system tolerance; immune unresponsiveness; immunological paralysis; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; Immunosuppressive Agents; Immunosuppressants; Immunosuppressive drug; Immunosuppressive treatment; immune suppressive agent; immune suppressor; immunosuppressive substance; immunosuppressor; Infection; keratinocyte; Kupffer Cells; Stellate Sinusoidal Macrophage; liver macrophage; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Liver; hepatic body system; hepatic organ system; Lysosomes; mortality; Mucous Membrane; Mucosa; Mucosal Tissue; Names; name; named; naming; Osteoporosis; Pain; Painful; Patients; Pemphigus; Pemphigus Vulgaris; Plasmapheresis; Therapeutic Plasma Exchange; Therapeutic Plasmapheresis; Quality of life; QOL; Reagent; Cell Surface Receptors; Relapse; Research; Research Design; Study Type; study design; Role; social role; skin lesion; Specificity; Steroids; Steroid Compound; Technology; Texas; Tissues; Body Tissues; Translating; Universities; Virus; Work; oligodendrocyte-myelin glycoprotein; MOG glycoprotein; myelin oligodendrocyte glycoprotein; Generations; Mediating; desmoglein 3; desmosomal glycoprotein 3; desmoglein III; Chimera Protein; Fusion Protein; Chimeric Proteins; improved; Procedures; Surface; Chronic; Clinical; Phase; mycophenolic acid morpholinoethyl ester; mycophenolate mofetil; Lesion; Endothelial Cells; Blood Serum; Serum; Funding; Dsg1 antigen; PFAN protein; Pemphigus foliaceus antigen; desmoglein 1; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; Antibody Therapy; Therapeutic; Infectious Agent; infectious organism; Inflammatory; Intravenous; rituximab; C2B8 Monoclonal Antibody; MabThera; Rituxan; Clinic; Reaction; Infusion procedures; Infusion; infusions; novel; new technology; novel technologies; General Population; General Public; Excision; Abscission; Extirpation; Removal; Surgical Removal; resection; Sampling; Property; Adverse event; Adverse Experience; Adverse effects; Skin; Pathogenicity; Molecular Interaction; Binding; preventing; prevent; ward; Address; Dose; Applications Grants; Grant Proposals; in vivo; Clinical Management; Process; Development; developmental; designing; design; new approaches; novel approaches; novel strategy; novel strategies; site targeted delivery; targeted delivery; experimental analysis; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; develop therapy; intervention development; treatment development; therapy development; commercialization; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; relapse patients; side effect; infection risk; death risk; mortality risk; Autoimmune; Immunoglobulin G autoantibodies; IgG autoantibodies

The overall goal of this project is to develop a novel therapeutic for the treatment of pemphigus. Pemphigus involves blistering of the skin or mucosal surfaces and can lead to difficulty in swallowing, very painful lesions, and a ~2-3 fold increased risk of mortality. About 90-95% of pemphigus cases can be accounted for by pemphigus vulgaris (PV) or pemphigus foliaceus (PF). Autoantibodies of the IgG class that are specific for desmogleins 1 and 3 (Dsg1 and Dsg3) disrupt the desmosomal-mediated adhesion of keratinocytes and are the causative agents of disease. PV can present as a mucosal-dominant form involving Dsg3-specific autoantibodies, or a form with both Dsg1- and Dsg3-specific autoantibodies that affects skin and mucosal surfaces. PF is a skin-dominant disease, involving only Dsg1-specific autoantibodies. Current treatments for pemphigus, such as the combination of corticosteroids and the B cell- depleting antibody, rituximab, have associated adverse effects such as osteoporosis and hypertension. In addition, the onset of action of rituximab takes several months since this therapeutic agent targets B cells, rather than the autoantibodies themselves. The combination of rituximab with tapered corticosteroids is also accompanied by a significant relapse rate (25-60%) and increased infection risk due to the immunosuppressive effects of B cell depletion. Other therapeutic approaches for pemphigus include the use of intravenous gammaglobulin, plasmapheresis or immunoadsorption, and can lead to undesirable side effects. Consequently, there is an unmet need to develop therapies for pemphigus that have rapid onset and high specificity for the autoantibodies. This application seeks to address the need for new and improved therapies for pemphigus by generating engineered, antibody-based reagents that specifically and rapidly deplete Dsg-specific antibodies. Importantly, these depleting agents are highly selective and do not affect the levels of other antibodies that have a protective role against infection. This first-in-class, novel technology has been named Seldeg technology (for selective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target Dsg-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. The proposed approach could be transformative for the management of pemphigus, and also has relevance to the use of Seldeg-based strategies for multiple other clinical settings where pathogenic antibodies cause disease.

Public Health Relevance Statement:
NARRATIVE Treatments that are currently available for antibody-mediated diseases such as the autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are generally immunosuppressive, are associated with adverse events and/or have limited efficacy. To address these issues, in this application we propose to develop a novel treatment that selectively removes the autoreactive antibodies which are involved in the disease process, without affecting the levels of other antibodies that are important for protection against infectious agents such as bacteria and viruses. This approach has the potential to be a game-changer for the clinical management of PV and PF. Terms: <21+ years old; 7S Gamma Globulin; Abscission; Acantholysis; Address; Adhesions; Adrenal Cortex Hormones; Adult; Adult Human; Adverse Experience; Adverse effects; Adverse event; Affect; After Care; After-Treatment; Aftercare; Antibodies; Antibody Therapy; Antigens; Applications Grants; Assay; Autoantibodies; Autoimmune; Autoimmune Diseases; B blood cells; B cell; B cells; B-Cells; B-Lymphocytes; B-cell; Bacteria; Binding; Bioassay; Biological Assay; Bleb; Blister; Blood Serum; Body Tissues; Bulla; Bullous Lesion; C2B8 Monoclonal Antibody; Cell Surface Receptors; Chimera Protein; Chimeric Proteins; Chronic; Clinic; Clinical; Clinical Management; Combined Modality Therapy; Corticoids; Corticosteroids; Deglutition; Desmosomes; Development; Disadvantaged; Disease; Disorder; Dose; Dsg1 antigen; Endothelial Cells; Engineering; Excision; Extirpation; Funding; Fusion Protein; Gamma globulin; General Population; General Public; Generations; Goals; Grant Proposals; Hypertension; IgG; IgG autoantibodies; Immune Tolerance; Immunoglobulin G; Immunoglobulin G autoantibodies; Immunologic Tolerance; Immunosuppressants; Immunosuppression; Immunosuppression Effect; Immunosuppressive Agents; Immunosuppressive Effect; Immunosuppressive drug; Immunosuppressive treatment; Infection; Infectious Agent; Inflammatory; Infusion; Infusion procedures; Intravenous; Kupffer Cells; Laboratories; Lead; Lesion; Liver; Lysosomes; MOG glycoprotein; MabThera; Macula Adherens; Mediating; Molecular Interaction; Mucosa; Mucosal Tissue; Mucous Membrane; Multimodal Therapy; Multimodal Treatment; Names; Node of Bizzozero; Osteoporosis; PFAN protein; Pain; Painful; Pathogenicity; Patients; Pb element; Pemphigus; Pemphigus Vulgaris; Pemphigus foliaceus antigen; Phase; Plasmapheresis; Procedures; Process; Property; QOL; Quality of life; Reaction; Reagent; Relapse; Removal; Research; Research Design; Rituxan; Role; Sampling; Serum; Skin; Specificity; Spot Desmosome; Stellate Sinusoidal Macrophage; Steroid Compound; Steroids; Study Type; Surface; Surgical Removal; Swallowing; Technology; Texas; Therapeutic; Therapeutic Plasma Exchange; Therapeutic Plasmapheresis; Tissues; Translating; Universities; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vesication; Virus; Work; acantholytic; adulthood; antibody based therapies; antibody treatment; antibody-based therapeutics; antibody-based treatment; autoimmune antibody; autoimmune condition; autoimmune disorder; autoimmunity disease; autoreactive antibody; combination therapy; combined modality treatment; combined treatment; commercialization; death risk; design; designing; desmoglein 1; desmoglein 3; desmoglein III; desmosomal glycoprotein 3; develop therapy; developmental; experimental analysis; heavy metal Pb; heavy metal lead; hepatic body system; hepatic organ system; high blood pressure; hyperpiesia; hyperpiesis; hypertensive disease; hypertensive disorder; immune suppression; immune suppressive activity; immune suppressive agent; immune suppressive function; immune suppressor; immune system tolerance; immune unresponsiveness; immunogen; immunological paralysis; immunosuppressive activity; immunosuppressive function; immunosuppressive response; immunosuppressive substance; immunosuppressor; improved; in vivo; infection risk; infectious organism; infusions; intervention development; keratinocyte; liver macrophage; mortality; mortality risk; mouse model; multi-modal therapy; multi-modal treatment; murine model; mycophenolate mofetil; mycophenolic acid morpholinoethyl ester; myelin oligodendrocyte glycoprotein; name; named; naming; new approaches; new drug treatments; new drugs; new pharmacological therapeutic; new technology; 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 technologies; novel therapeutics; novel therapy; oligodendrocyte-myelin glycoprotein; post treatment; prevent relapse; relapse patients; relapse prevention; resection; rituximab; self reactive antibody; side effect; site targeted delivery; skin lesion; social role; study design; targeted delivery; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; therapy development; treatment development; ward; γ globulin