Bispecific Antibodies Directed to CD3and HBsAg to Treat Chronic Hepatitis B Virus

ABSTRACT Chronic HBV infectionsCHBare a major global health concernWhile multiple treatment options exist for CHBthey are rarely curativeScientific focus is now shifting towards CHB cure researchbut curative treatments have remained elusive due to persistence of covalently closed circular DNAcccDNAin infected hepatocytes despite anti viral therapiesproviding the template for further viral replicationsCHB patients exhibit narrowly focused T cell responses and HBV immunotoleranceresulting in failure of conventional vaccination approachesHowevercurative clinical results from bone marrow transplantations and T cell based immunotherapeutic strategies in CHB animal modelsindicate T cells can potentially control or clear CHBT cell redirecting bispecific Abs are the most potent type of therapeutic Abs to dateshowing durable and high response rates in hard to treat cancersHBV surface antigenHBsAgspecific T BsAbs were successfully tested in animalsshowing effective elimination of infected cells in vitro and in vivoHoweverthese T BsAbs do not cross react with primate T cellslimiting their testing viabilityand or include strong T cell activation and high cytokines production with significant toxicityTeneoBio developed a one of a kind platform based on a fully human heavy chain only AbsUniAbsa high throughput NGS based bioinformatics pipelineTeneoSeekand proprietary UniAb producing animalsUniRatsThe fully humanheavy chain only structure of UniAbs facilitates multivalent binding for potent and specific kill of cells with low antigen densitiespromotes stabilityeven at extreme temperature and pH conditionsand predicts a superior safety profileImportantlywe have used it to develop a novel type ofCDmoiety that mediates selective cell kill with minimal cytokine secretion and preferential effector T cells activationthus avoiding patient borne toxicityIn this programTeneoBio scientists will join forces with expert HIV and HBV virologists and immunologists at Oregon Health andampScience University to harness these innovations towards developing a best in class trivalent T BsAbs with biparatopic targeting of HBsAg on infected cells together with a uniqueCDmoiety that reacts with both human and rhesus macaque T cells with the goal of activating adjacent T cell and degrading the nuclear cccDNA reservoirIn Specific AimUniRats will be immunized with HBsAgthe universally effective Recombivax HB vaccineto generate a high titer anti HBV responseThenUniRatslymph nodes will undergo high throughput NGS identification ofputative high specificity and affinity UniAbs leads against HBsAgIn Specific Aimsequence families identified in SAwill be cloned and expressedcharacterized for manufacturabilityspecificityand affinity in primary functional screensthen tested for binding to surface expressed HBsAg on HBV infected human and rhesus macaque primary hepatocytesPhase II will focus on generating T BsAbs comprised of rhesus macaque human cross reactivelow agonistCDmoiety and five differentHBV moieties selected in Phase Ifor in vitro and in vivo studiesPut togetherthese studies will allow us to file an IND application and to initiate Phase I clinical trials NARRATIVE Chronic Hepatitis BCHBinfections are a major global health concern affecting millions worldwide and causingdeaths annuallyWhile multiple treatment options exist for CHBthey are rarely curativeThis project aims at developing a best in class therapeutic antibody against Hepatitis B that targets infected cells and directs the body s immune cells to eliminate themThis antibody will be developed using TeneoBio s unparalleled platform of fully human antibodies produced in rats and identified via computational and experimental pipeline