Effective Nanoantibodies as Promising Therapeutics for Treating Sepsis

PROJECT SUMMARYABSTRACTThe innate immune system releases multiple inflammatory cytokines in response to pathogens and their toxins to combat infectionSepsis and septic shock develop when such inflammatory response becomes overwhelming and uncontrolledresulting in significant capillary leakagetissue edemaorgan failure and deathThe vascular endothelial barrier dysfunction resulting from massive endothelial cellECdeath or disassembly of adherence junctionsAJsis a primary pathological feature of sepsisRestoration of the endothelial barrier by inhibiting inflammation induced AJs disassembly and wide spread EC apoptosis is essential for resolving endothelial hyper permeabilitythus represents a promising therapeutic approachWe have obtained strong preliminary data showing that inhibition of TNFthe principal mediator of inflammatory effects during sepsisby a single domain VHH nanoantibodynAbwe identified from phage display library significantly strengthened endothelial barrier function and greatly promoted survival in two sepsis mouse modelsMore importantlythe therapeutic effect of the engineered nAb multimers and fusions with another nAb for longer in vivo half life were even more promising in sepsis models and clearly superior to that of conventional monoclonal anti TNFantibody Humirawhich is widely used for the treatment of autoimmune diseases and previously tested for treating sepsisBased on our supporting datawe posit that the new generation of engineered anti TNFnAbs in our hands have very good potential to be developed into a novel therapeutics for treating sepsisIn the proposed Phase I SBIR studieswe will apply a multidisciplinary approach to further define the efficacy of the main choice of our anti TNFnAb and it s humanizedmultivalent version in promoting survival after sepsis induction in miceunderstand its functions in strengthening endothelial barrier function and the resultant improved multiple organ functionand subject it for commercial potential assessment aimed at developing a clinical applicable new medicine to treat sepsis NARRATIVEStrengthening endothelial barrier function by blocking inflammation mediated massive EC death and AJs disassembly in sepsis is essential for survivalWe study this possibility by inhibition of TNFthe master regulator of inflammationusing new generation of engineered nanoantibodiesnAbsWe will investigate the therapeutic effect of nAb mediated TNFinhibition that may have an essential role in the restoration of vascular endothelial barrier function in severe inflammatory related septic injury and commercial develop these nAbs to clinical applicable anti sepsis medicine