Development of an Fr? x Fr? x CD3 trivalent, biparatopic T-cell engaging antibody to treat high grade serous carcinoma

ABSTRACT In this project we propose to develop a first in class therapeutic antibodyAbagainst high grade serous carcinomaHGSCcomposed of two domains that simultaneously target separate epitopesbiparatopicof the FRantigen coupled to a unique T cell activating anti CDmoiety that mediates tumor kill with minimal cytokine secretion and preferentially activates effector over regulatory T cellsHGSC is the leading cause of gynecologic cancer mortality in womenwithnew diagnoses anddeaths per year and andltoverall survival in advanced stage diseaseThusthere is an urgent medical need for novelparadigm shifting therapiesNumerous studies have shown that folate receptorFRis highly overexpressed in HGSCwhereas it is absent or minimally expressed in normal tissuesAs such several Ab based therapies targeting FRhave been developedmost notably T cell redirecting bispecific AbsT BsAbsapproaches that have shown some efficacyHoweverin HGSC these approaches have been hampered by toxicity including cytokine release syndromeCRSand formation of anti drug immune responsesTeneobio makes fully human heavy chain only AbsUniAbsusing a unique high throughput next generation sequencingNGSbased bioinformatics pipelineTeneoSeekand proprietary UniAb producing animalsUniRatsthat enable development of novel therapeutics by combining different mechanisms of action to address common impediments in the development of therapeutic AbsThe fully human heavy chain only structure of UniAbs facilitates multivalency and promotes stability and potentially limits anti drug immune response concernsas demonstrated by our BCMAxBCMAxCDtrivalentbispecific Ab that is on track to enter the clinic this yearMost importantlywe have used TeneoSeek to develop a novelCDAb that mediates tumor kill with minimal cytokine secretionpotentially limiting CRSand preferential activation of effector over regulatory T cellsFor these reasonswe hypothesize that a trivalent T BsAb with biparatopic targeting of FRcoupled to our novelCDmoiety will provide high specificity with minimal cytokine secretionpotentially creating a safe and effective therapy for HGSCIn this application we will use our platform to identify two anti FRmoieties with optimal functional characteristics targeting non overlapping epitopescombine them with our selectively activatingCDdomainand select for the candidate with optimal safety and efficacy in in vitroin vivo and ex vivo models of HGSCIn Specific Aimwe will use TeneoSeek to identify several hundred putative FRspecific Ab sequence familiesFrom among them we will identify UniAbs that bind non overlapping epitopes with optimal functional characteristicsusing astep functional screen and competitive binding experimentsIn Specific Aimsandwe will combine two of these binding domains specific for non overlapping epitopes with our unique selectively activatingCDmoiety and choose a lead with optimal safety and efficacy in in vitroin vivo and ex vivo models of HGSCAt the conclusion of Phase Iwe will be ready to perform PK and IND enabling studies in NHP in preparation for an IND filing and Phaseclinical trials in HGSC patients NARRATIVE High grade serous carcinomaHGSCis the leading cause of gynecologic cancer mortality in womenTherapeutic options for HGSC are limited with andltoverall survival in advanced stage diseaseWe propose to develop an antibody therapy for HGSC that combines two highly specific heavy chain only antibody domains against non overlapping epitopes of a tumor specific antigen with a unique T cell activating domain to generate a novel therapy with reduced toxicityimproved efficacy and a widened therapeutic window