Development of a PSMA x PSMA x CD3 trivalent, bispecific T-cell engaging antibody to treat Castration Resistant Prostate Carcinoma

Abstractdeaths from prostate cancerCaPare anticipated inin the US alonein one large trial it was shown that up toof deaths due to CaP occurred in patients with metastatic disease at diagnosisThese patients are treated with androgen deprivation therapy but invariably progress to castration resistant cancerCRPCwhich has limited therapeutic options and none that extend median overall survival of overmonthsIn CaPtumor cells express several highly prostate specific surface proteins ideally suited for antibodyAbtargeting such as prostate specific membrane AgPSMAagainst which high affinity Abs have been raisedbut with limited anti tumor efficacyBetter efficacy has been demonstrated with T cell redirecting approaches which include T cell redirecting bispecific AbsT BsAbsand chimeric antigen receptor T cellsCAR Tthat induce the body s own T cells to kill the tumorHoweverthere still remains the unsolved issue of strong T cells activation leading to dose limiting toxic immune activationincluding cytokine release syndromeCRSThe overall goal of the proposed project is to develop a T BsAb against PSMA that combines our innovations ofa novelfirst in classPSMA heavy chain only AbUniAbanda unique activating anti CDdomain that induces killing with minimal cytokine secretion and preferential activation of effector over regulatory T cellsThis molecule is expected to show high specificityreduced toxicity and a widened therapeutic windowThe heavy chain only structure of UniAbs facilitates multivalencyas demonstrated by our BCMAxBCMAxCDtrivalentbispecific Ab currently undergoing IND enabling in vivo studies in multiple myelomaand on track to enter the clinic inUsing our proprietary UniAb producing ratsUniRatstogether with our unique NGS based bioinformatics pipelineTeneoSeekwe have previously identified high affinity anti PSMAPSMAAb families demonstrating PSMA binding and shown to mediate killing of prostate tumor cell lines in vitro and in vivoIn this proposed study we will perform diversity screening to identifyPSMA UniAbs with optimal functional characteristics for the construction of a therapeutic moleculeFrom the previously identified familieswe will select the most suitablehighest affinity Ab leads using competitive binding experimentsdiversity screeningand functional characterizationspecific aimNextwe will identify the leads with optimal safety and efficacy characteristicsThe leads will be cloned into T BsAb constructs together with Teneobio s low activatingCDmoiety and evaluated in vitro and in vivo models of CaP for killing specificity of PSMA positive tumor cellsas well as off target activationspecific aimFinally we will identify the leads with optimal safety and efficacy characteristics in ex vivo models of CaPwhere the leads will be assessed for cytotoxicityT cell activation and cytokine releasespecific aimIn future workthe lead molecule will be advanced into IND enabling studies including rodent and Cynomolgus PK studiestissue cross reactivityand evaluation of anti drug Abs in preparation for an IND filing and phaseclinical trials in CRPC patients Narrative Castration resistant prostate cancerCRPCis the most lethal form of prostate carcinomaTherapeutic options for CRPC are limited and none extend median overall survival greater thanmonthsWe propose to develop a novel bispecific T cell redirecting antibody therapy for CRPC that combines our innovations of a highly specific heavy chain only antibody against a tumor specific antigen and a unique T cell activating domain for reduced toxicity and a widened therapeutic window