Antitumor and anti-infectious disease vaccines require adjuvants in order to obtain optimal immunogenicity and therapeutic and protective efficacy. QS-21 is a natural saponin fraction that significantly out-performs other adjuvants in eliciting productive antibody and T-cell responses. It has remained the adjuvant of choice and has proven it's potency as immunological adjuvant in many cancer, infectious disease and degenerative disorder vaccine trials. Problems that have hampered the further development of QS-21 include adverse biological effects (that limit the tolerable dose), chemical instability, scarcity of the Quillaja saponaria tree (from which QS-21 is extracted) and variability of harvest yields from these trees. Recently, all of these liabilities have been overcome by our semisynthetic approach to QS-21 synthesis. This synthesis has also made molecular building blocks readily available for synthesis of modified and truncated QS-21 analogues. The replacement of unstable linkages within the native saponin with chemically robust functional groups has enhanced molecular stability. Structural variants incorporating systematic simplification of the peripheral sugar moieties and of the acyl chain substructure have aided in determining the minimal structural requirements for safety and potent adjuvant activity, and have decreased the required number of synthetic steps by over 50% from fully synthetic QS-21 (SQS-21) to our lead synthetic analogues. These efforts (now completed) have resulted in selection of the optimal QS-21 analogue TiterQuil-1-0-5-5 for more formal preclinical development because of its simplified structure, improved stability, consistent potency and attenuated toxicity. The core intellectual property is our Triterpene Saponin Synthesis Technology (TriSST) platform covering both the method of synthesis as well as novel compositions of matter under the patent application """"""""TRITERPENE SAPONINS, METHODS OF SYNTHESIS, AND USES THEREOF"""""""" application number 12/420,803 as well as our proprietary semisynthetic technology which is protected by US patent U.S. Patent No. 8,283,456. TriSST was developed by Dr. David Gin et al at Memorial Sloan-Kettering Cancer Center (MSKCC) and this technology has been exclusively licensed by Adjuvance Technologies, Inc. TriSST is a highly convergent synthetic approach in which the four domains in QS-21 (branched trisaccharide + triterpene + linear tetrasaccharide + fatty acyl chain) are synthesized separately and then assembled to produce the target molecule. Each of the domains can be modified independently and then combined to produce a virtually infinite number of rationally designed QS-21 analogs. Initially fully synthetic QS-21(SQS-21) was shown to be safe and immunologically active in a Phase 1 clinical trial. We then used TriSST to prepare and test over 100 novel analogues in a systematic sequential series of studies. Our model for evaluating QS-21 and analogues has involved KLH-conjugate vaccines against a series of peptide and carbohydrate cancer antigens, measurement of antibody responses against these antigens, and in some cases measurement of T-cell responses against MUC1 and KLH. Results in these several assays have tracked in parallel with no consistent outliers. The potency of selected analogues has been confirmed against novel Lyme fever OspC peptides and pneumococcal Prevnar 13 vaccines. Here we propose to further develop TiterQuil-1-0-5-5 for clinical use by scaling up synthesis in an independent facility. At the conclusion of these studies we will have demonstrated that TiterQuil-1-0-5-5 synthesis can be scaled up to near commercially required levels and that it has improved purity, stability, safety, ease of manufacture, and immunologic potency (using an expanded panel of antigens more relevant for infectious disease vaccines) when compared to natural or synthetic QS-21. This will provide the basis for a Phase 2 SBIR application supporting a TiterQuil-1-0-5-5 drug master file (DMF) and its wider use in vaccines that target diverse public health concerns.
Specific Aim 1 : Synthesize 2 grams of truncated QS-21 analogue TiterQuil-1-0-5-5, a sufficient quantity for Aims 2 and 3.
Specific Aim 2 : Confirm purity, stability and erythrolytic capacity of this scaled up batch of TiterQuil-1- 0-5-5, and perfrm a formal pharmacology/toxicology study as required for a DMF application.
Specific Aim 3 : Compare the immunologic potency and safety of TiterQuil-1-0-5-5 with natural and synthetic QS-21(SQS-21) using vaccines targeting OspC peptide as well as the commercially available pneumococcal conjugate Prevnar-13.

Public Health Relevance

Despite the tremendous advances in vaccinology, in the United States there are only two vaccine adjuvants approved for use. QS-21 is one of the most promising investigational adjuvants, but it is hampered by adverse characteristics that limit it's further development, such as intolerability, chemical instability, and scarcity. These liabilities have been overcome by our semisynthetic approach to saponin adjuvants which have aided in determining the minimal structural requirements for safety and potent adjuvant activity, and have decreased the required number of synthetic steps by over 50% from fully synthetic QS-21 (SQS-21) to synthetic analogues that are scalable, non-toxic and reliably manufactured.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-IMST-L (11))
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GU, Xin-Xing
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Adjuvance Technologies, Inc.
New York
United States
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