Large Scale Synthesis of the Next Generation Synthetic Saponin Adjuvant TiterQuil

PROJECT SUMMARY Vaccines against infectious diseases continue to improve public health across the worldWith increased knowledge of etiologic pathogens and necessary immune responses have come increasingly safe and defined or targeted vaccinesThe success of defined vaccines requires use of an immunological adjuvant to permit more effective immunizationFew adjuvants have sufficient potency and acceptable toxicity for clinical userestricting the potency of some vaccines and requiring higher or more doses of othersA leading adjuvant candidate is the natural product QSwhich has been used in numerous clinical settings despitemajor liabilitiesdose limiting toxicitypoor stabilityand limited availability of quality productTo address these liabilitiessupported by RO s at Memorial Sloan Kettering Cancer CenterMSKCCwe developed new synthetic strategies that permitted synthesis of QSand purposefully engineered QSanalogsAdjuvance Technologies Incis a privately held biopharmaceutical company formed to bring the potential of this synthetic saponin technology to clinical fruitionThis technology has permitted systematic modification of the separate chemical domains of QSfor increased tolerability and immunological potencyAdjuvance has licensed and patented this technology and used it to design analogues with improved potency toxicity ratios compared to QSwhile decreasing the required number of synthetic stepsTiterQuilwas selected as optimal and the focus of our Phase I SBIR application from overrationally designed Adjuvance moleculesIneach of themajor QSliabilities has been eliminatedWork accomplished under the Phase I SBIR demonstrated that our selected CMOAlbany Molecular Research IncAMRIwas able to preparein batches as large asmgs and that these batches had the requisite purity and diminished toxicity demonstrated previously with smaller batches prepared in laboratories at MSKCCFinally these batches ofcontinued to surpass QSin augmenting antibody titers against a variety of antigens in the absence of the toxicity seen with QSThe goals of this Phase II SBIR application are to perform the steps required for wider preclinical use and to generate the data necessary to complete an Investigational New DrugINDapplication to the U SFDAIf production of consistently purestablesafe and widely effective material at scale is successful in the work proposed hereAdjuvance plans to distributewidely to collaborators and under separate funding conduct a Phase I clinical trial with acellular pertussis vaccine plusWe address here the concerns raised by potential commercial partnersas well as BARDADoD and the NIHcommercial scalability and costpossible toxicityand applicability to use with more widely used immunological carriers and antigensThese will all be addressed as we take the steps necessary to be able to conduct the initial Phase I clinical trial with