Vaccines against infectious diseases continue to improve public health across the world. With increased knowledge of etiologic pathogens and necessary immune responses have come increasingly safe and defined or targeted vaccines. The success of defined vaccines requires use of an immunological adjuvant to permit more effective immunization. Few adjuvants have sufficient potency and acceptable toxicity for clinical use, restricting the potency of some vaccines and requiring higher or more doses of others. A leading adjuvant candidate is the natural product QS-21 which has been used in numerous clinical settings despite 3 major liabilities: dose limiting toxicity, poor stability, and limited availability of quality product. To address these liabilities, supported by RO1s at Memorial Sloan-Kettering Cancer Center (MSKCC), we developed new synthetic strategies that permitted synthesis of QS-21 and purposefully engineered QS-21 analogs. Adjuvance Technologies Inc. is a privately held biopharmaceutical company formed to bring the potential of this synthetic saponin technology to clinical fruition. This technology has permitted systematic modification of the separate chemical domains of QS-21 for increased tolerability and immunological potency. Adjuvance has licensed and patented this technology and used it to design analogues with improved potency/toxicity ratios compared to QS-21 while decreasing the required number of synthetic steps. TiterQuil-1-0-5-5 (1055) was selected as optimal and the focus of our Phase I SBIR application from over 100 rationally designed Adjuvance molecules. In 1055 each of the 3 major QS-21 liabilities has been eliminated. Work accomplished under the Phase I SBIR demonstrated that our selected CMO, Albany Molecular Research Inc. (AMRI), was able to prepare 1055 in batches as large as 600 mgs and that these batches had the requisite purity and diminished toxicity demonstrated previously with smaller batches prepared in laboratories at MSKCC. Finally these batches of 1055 continued to surpass QS-21 in augmenting antibody titers against a variety of antigens in the absence of the toxicity seen with QS-21. The 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 Drug (IND) application to the U.S. FDA. If production of consistently pure, stable, safe and widely effective material at scale is successful in the work proposed here, Adjuvance plans to distribute 1055 widely to collaborators and under separate funding conduct a Phase I clinical trial with acellular pertussis vaccine plus 1055. We address here the concerns raised by potential commercial partners, as well as BARDA, DoD and the NIH: commercial scalability and cost, possible toxicity, and applicability to use with more widely used immunological carriers and antigens. These will all be addressed as we take the steps necessary to be able to conduct the initial Phase I clinical trial with 1055.
Currently available immunological adjuvants have insufficient potency or unacceptable toxicity, restricting the potency of many vaccines and requiring higher or more doses of others. In this Phase II SBIR, Adjuvance Technologies will demonstrate that NCSS batches of its semi-synthetic saponin adjuvant TiterQuil-1-0-5-5 (1055) can be inexpensively prepared and that its potency and safety with a variety of antigens remains unmatched. Once this is confirmed, 1055 could be used to augment the potency of the majority of standard commercial vaccines as well as a range of experimental vaccines investigated at BARDA, DoD, the NIH, and internationally.