The overall goal of this project is to develop a novel therapeutic for the treatment of autoimmuneatypical hemolytic uremic syndrome (aHUS). Autoimmune aHUS is a rare, life-threateningdisease that affects both children and adults. It is caused by autoantibodies that recognize thenegative regulator of the alternative complement pathway, factor H (FH). FH-specific antibodiesboth block FH activity and result in FH depletion. The dysregulated complement activation thatensues results in microangiopathic hemolytic anemia, thrombocytopenia and acute kidneydamage that can culminate in renal failure. Although there are currently several therapies for autoimmune aHUS, all of these lead togeneral immunosuppression and other severe side effects. For example, plasma exchangeresults in adverse consequences in a high percentage of patients. The more recently developeduse of antibodies such as eculizumab that are specific for complement component C5 hasbeneficlal therapeutic effects. However, C5 blockade also substantially increases the risk ofinfection by pathogens that include meningococci and pneumococci. In addition, the underlyingcause of disease, namely the levels of FH-specific antibodies are not affected by complementblockade. The risk of recurrence following discontinuation of C5-targeted therapy is thereforehigh, and such recurrence is usually severe and rapid. As a result of the limitations of existing therapies for autoimmune aHUS, there is a need forthe development of therapeutics that target the pathogenic antibodies. This application seeks toaddress this need by generating engineered, antibody-based reagents that specifically and rapidlydeplete FH-specific antibodies, whilst not affecting the levels of antibodies that have a protectiverole against infection etc. This first-in-class, novel technology is called Seldeg technology (forselective degradation). The Specific aims of the study are: 1. To design and express Seldegs to target FH-specific antibodies. 2. To analyze the stability and binding activity of the Seldegs. This approach could not only be transformative for the management of this potentiallydevastating disease, but would also lay the foundations for analogous approaches to be taken inmany other clinical settings where pathogenic antibodies lead to disease. PROJECT NARRATIVE
Current treatments for antibody-mediated autoimmunity suffer from having effects that are
generally immunosuppressive and increase the risk of potentially life-threatening infections by
pathogens such as bacteria and viruses. To overcome these problems, this proposal seeks to
develop a novel treatment to selectively remove the causal agent of disease, namely the
autoreactive antibodies, without affecting the levels of other antibodies that provide protection
against infectious agents. Such an approach has the potential to be transformative for the
treatment of antibody-mediated autoimmunity. Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Hemolytic Anemia ; Antibodies ; Antigens ; immunogen ; Autoantibodies ; autoimmune antibody ; autoreactive antibody ; self reactive antibody ; Autoimmune Diseases ; autoimmune condition ; autoimmune disorder ; Autoimmunity ; Autoimmune Status ; Bacteria ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Cells ; Cell Body ; Child ; 0-11 years old ; Child Youth ; Children (0-21) ; youngster ; Chronic Disease ; Chronic Illness ; chronic disorder ; Complement ; Complement Proteins ; Complement component C5 ; Complement 5 ; Complement C5 ; Complement Component 5 ; Complement Activation ; complement pathway regulation ; Alternative Complement Pathway ; Properdin Pathway ; Cyclophosphamide ; CTX ; CYCLO-cell ; Carloxan ; Ciclofosfamida ; Ciclofosfamide ; Cicloxal ; Clafen ; Claphene ; Cycloblastin ; Cycloblastine ; Cyclophospham ; Cyclophosphamidum ; Cyclophosphan ; Cyclophosphane ; Cyclophosphanum ; Cyclostin ; Cyclostine ; Cytophosphan ; Cytophosphane ; Cytoxan ; Endoxan ; Endoxana ; Enduxan ; Fosfaseron ; Genoxal ; Genuxal ; Ledoxina ; Mitoxan ; Neosar ; Procytox ; Sendoxan ; Syklofosfamid ; Zytoxan ; Disadvantaged ; Disease ; Disorder ; Engineering ; Foundations ; Goals ; Hemolytic-Uremic Syndrome ; Gasser's Syndrome ; Immune Tolerance ; Immunologic Tolerance ; immune system tolerance ; immune unresponsiveness ; immunological paralysis ; Immunosuppression ; Immunosuppression Effect ; Immunosuppressive Effect ; immune suppression ; Immunosuppressive Agents ; Immunosuppressants ; Immunosuppressive drug ; Immunosuppressive treatment ; immune suppressive agent ; immune suppressor ; immunosuppressive substance ; immunosuppressor ; Infection ; Kupffer Cells ; Stellate Sinusoidal Macrophage ; liver macrophage ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Liver ; hepatic body system ; hepatic organ system ; Lysosomes ; Meningococcal Infections ; Multiple Sclerosis ; Disseminated Sclerosis ; insular sclerosis ; Nasopharyngitis ; Neisseria meningitidis ; Meningococcus ; N meningitidis ; N. meningitidis ; Patients ; Plasma Exchange ; Reagent ; Cell Surface Receptors ; Recurrence ; Recurrent ; Relapse ; Kidney Failure ; Kidney Insufficiency ; Renal Failure ; Renal Insufficiency ; Research ; Risk ; Role ; social role ; Streptococcus pneumoniae ; D pneumoniae ; D. pneumoniae ; Diplococcus pneumoniae ; Pneumococcus ; S pneumoniae ; S. pneumoniae ; Technology ; Texas ; Thrombocytopenia ; Thrombopenia ; Thrombosis ; thrombotic disease ; thrombotic disorder ; Tissues ; Body Tissues ; Translating ; Universities ; Upper Respiratory Infections ; Upper Respiratory Tract Infection ; Virus ; Work ; blocking factor ; Complement Factor H ; Factor H ; Generations ; Mediating ; Chimeric Proteins ; Chimera Protein ; Fusion Protein ; base ; Organ ; Surface ; Acute ; Clinical ; Phase ; Variant ; Variation ; Endothelial Cells ; Serum ; Blood Serum ; Childhood ; pediatric ; Funding ; Onset of illness ; disease onset ; disorder onset ; Antibody Therapy ; antibody based therapies ; antibody treatment ; antibody-based therapeutics ; antibody-based treatment ; infectious organism ; Infectious Agent ; Inflammatory ; Life ; Frequencies ; Event ; Clinic ; antibody titering ; Antibody titer measurement ; Host Defense ; disease severity ; Severity of illness ; novel ; novel technologies ; new technology ; Cell surface ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; Sampling ; Property ; Adverse Experience ; Adverse event ; unpublished works ; Central Vein ; Pathogenicity ; Pathogenicity Factors ; Virulence Factors ; Molecular Interaction ; Binding ; Address ; Dose ; Grant Proposals ; Applications Grants ; in vivo ; Immunologics ; Immunochemical Immunologic ; Immunologic ; Immunological ; Immunologically ; Therapeutic Effect ; Pathway interactions ; pathway ; autoreactivity ; design ; designing ; novel strategies ; new approaches ; novel approaches ; novel strategy ; targeted delivery ; site targeted delivery ; pathogen ; Population ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; therapeutic target ; therapeutic development ; therapeutic agent development ; adverse outcome ; adverse consequence ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; side effect ; infection risk ; renal damage ; damage to kidney ; kidney damage ; Autoimmune ;
