Advancing a Candidate Human Polyclonal Anti-Thymocyte Globulin Product Produced in Transchromosomal Bovine for Transplant Induction/Acute Rejection and T1D Therapy

Project Summary Abstract Currently available anti thymocyte globulinATGproducts are polyclonal animal antibodiesATGAMequine polyclonal ATGThymoglobulinrabbit polyclonal ATGand have found broad use as immune tolerizing agentsparticularly for induction therapy in a majority of tissue transplantsfor acute transplant rejectionand as treatment for graft vshost disease following bone marrow transplantsEarly clinical trials also suggest ATG may have a role in immunomodulation to treat the underlying autoimmunity of typediabetesT DHoweveranimal derived ATG products can result in serum sicknessdays after administration as the recipientandapos s immune system reacts to these xenobiotic immunoglobulinsrendering any subsequent redosing particularly problematicAn agent that could combine the beneficial effects of the current animal ATG products but avoid the xenobiotic responses would bring significant advantages to each of these therapeutic areasThis proposal seeks to produce potent fully human ATG polyclonal antibodies by immunizing transchromosomal bovinesTcBswith human thymocytes in combination with a strong adjuvant and immune stimulatorTcB derived fully human polyclonal ATG antibodiesSABwill have potent activity and would eliminate the risk of anaphylaxis and serum sickness associated with xenobiotic IgG productsSuccess of this proposal will result in an IND filing that will facilitate a Phaseclinical trial to evaluate safetytolerabilityand efficacyPrevious studies have demonstrated that TcBs can produce large amounts of human polyclonal antibodies with extremely high titers and neutralizing activity against various antigensincluding virusesproteinsbacteriaand whole cell antigens following multiple immunizationsA phase I clinical trial has shown that the human antibody products produced by TcBs are safe and well tolerated in healthy subjectsClinicalTrials gov NCTIn this proposalSAB BiotherapeuticsIncSABand Sanford Research intend to expand our earlier proof ofconcept studies to produce a human ATG polyclonal antibody productSABusing SABandapos s innovative human antibody production platform technologydiversitAband evaluate the antibodies in pre clinical studiesThere are two phases in this projectPhaseEvaluate and compare SABwith ATGAM and Thymoglobulin for direct cytotoxicity toward conventional T cellsExamine SABaffinity toward red blood cellsRBCsand evaluate the effects of RBC adsorption on SABbinding to peripheral blood mononuclear cellsandEvaluate and compare SABwith ATGAM and Thymoglobulin for binding affinity to multiple subsets of PBMCsPhaseProduction of two na ve TcBs for SABproductionImmunization and plasma collection from TcBs for SABproductionPurification of a pre clinical lot and a clinical lotcGMPof SABfor use in AimsandDevelop and qualify a target specific potency assay based on the results of the phase I aimsandComplete IND enabling pre clinical evaluation of SABProject Narrative The research proposed in this application seeks to produce a fully human anti thymocyte globulinATGproductSABin transchromosomal bovines that express human polyclonal antibodies for transplant induction acute rejection therapy and potential immunomodulation therapy to treat the underlying autoimmunity of typediabetesas suggested by early clinical trial resultsSABwill combine the beneficial effects of current animal derived ATG productswhile eliminating the risk of anaphylaxis and serum sickness associated with xenobiotic IgG administrationDevelopment of SABwill bring significant advantages to each of the established ATG therapeutic areaswhile advancing our understanding of the underlying autoimmunity of T D