Pemphigus-specific T cell engagers for pemphigus targeted immunotherapy

ABSTRACTPemphiguspemphigus vulgarisPVand pemphigus foliaceusPFis an acquired autoimmune disease in which IgG antibodies target the keratinocyte desmosomal cadherin proteins desmogleinand desmogleinresulting in intraepithelialmucocutaneous blisteringNearly all PV and PF patientsbut no unaffected individualsdemonstrate detectable anti DSGand anti DSGreactivityrespectivelyPV is a potentially fatal autoimmune disorder with a mortality rate ofon average without treatment with corticosteroidsCurrent methods for pemphigus treatment require general immune suppression to reduce overall antibody productionbut this approach impairs protective immune responseswhich can lead to potentially fatal infections and secondary cancersWe propose a novel approach for targeted immunotherapy of PV by directing patientandapos s T cells to specifically seek out and kill the pemphigus specific B cellswhile sparing the beneficial immune cells that protect from infectionAs a proof of principlein phase IMulti specific T cell Engagers or MuTEIgG like recombinant proteins consisting of a well characterized anti CDantibody OKTwith mutated human IgGFcand human desmogleinand desmogleinextracellular domains will be producedThe T cell mediated target elimination of anti desmoglein specific B cells by MuTE will be validated in cell based assays and in mouse modelsPhase II work will focus on scale up of biologics productionobtaining the preclinical in vivo pharmacodynamicspharmacokinetics and toxicity data in animal models necessary for submission of an IND NARRATIVEPemphigus vulgaris is a potentially fatal autoimmune diseaseCurrent methods for pemphigus treatment impair protective immune responseswhich can lead to potentially fatal infections and secondary cancersOur novel targeted immunotherapy for PV is designed to direct patientandapos s T cells to specifically seek out and kill the pemphigus specific B cellswhile sparing the immune cells that protect from infection