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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ADJUV-ANT VACCINES (Elucidating the Molecular Mechanisms of Synthetic Saponin Adjuvants and Development of Novel Self-Adjuvanting Vaccines)

Teaser

Summary

Adjuvants are substances added to vaccines to make them work better, leading to more potent immune responses. Despite their key role, few adjuvants combine potent activity and low toxicity for further clinical advancement. Moreover, their mechanisms of immune-potentiation are poorly understood. Modern vaccine strategies based on weakly immunogenic carbohydrate antigens have not yet been fully successful in anti-cancer therapy, and the development of an effective carbohydrate-based cancer vaccine is still under investigation. The saponin natural product QS-21 has shown promise as a potent vaccine adjuvant in a number of clinical trials, but suffers from inherent limitations such as scarcity, dose-limiting toxicity and an unknown mechanism of action. This project aims to use chemistry to address clear gaps in the adjuvant/vaccine field with extraordinary chemical precision. The objectives of this project are (1) the development of improved, synthetically accessible saponin-based adjuvants and chemical probes and their application for (2) the construction of more efficient carbohydrate-based synthetic vaccines and (3) the elucidation of their molecular mechanisms of action.
The molecular-level investigations performed with the synthetic saponin probes will address fundamental immunological and mechanistic questions on how these saponin constructs potentiate the immune response, advancing the frontiers of knowledge and enabling the rational design of improved adjuvant-antigen combinations for vaccines. The project will also provide new chemical approaches and synthetic access to clinically relevant molecules that will lead to critical advances in vaccine development with the potential to translate into the clinic. Therefore, in addition to its scientific impact there is no doubt of the key socioeconomic impact of this project for the society bridging the gap between basic science and more applied, translational research, with its important implications in human health.

Work performed

The tasks performed within this timeframe have included the preparation of promising saponin variants derived from the QS-21 immunoadjuvant in a fully-protected form. These tasks comprised synthesis of the different monosaccharide building blocks, their assembly using a range of glycosylation reactions and further attachment to other fragments of the molecule, i.e. the triterpene core and the acyl side chain.

The saponin analogues were designed on the basis of my previous structure-activity relationship studies on the QS-21 structure. They included a linear polar acyl chain, several types of triterpene and functionalities at the central glycosidic linkage, and different terminal disaccharides at the linear oligosaccharide domain of the molecule.

Based on previously identified truncated saponin variants with potent adjuvant activity and differing toxicity profiles, we first focused on the preparation of new promising molecules with subtle structural modifications with the goal of discovering even more potent and less toxic adjuvants. The synthesis followed the original convergent approach and has been successfully performed so far, pending global deprotection and HPLC purification. Another important objective for this period has been the synthesis of oligosaccharide saponin variants to explore the effect of carbohydrate residues on adjuvant activity and to access potentially active streamlined saponin adjuvants. The fully protected oligosaccharide variants have been synthesized using the more recent divergent approach that I recently developed.
Moreover, modified acyl chains incorporating chemical handles and tags have been designed and are being synthesized to incorporate them into the saponin scaffold as probes for future mechanistic studies.

Finally, we have also started the synthesis of model peptide immunogens and a number of cancer-associated carbohydrate antigens for use in a mouse vaccination model. Immunological studies with related synthetic constructs have also been performed and are currently underway in close proximity to a CIC bioGUNE immunologist.

Final results

Pending the late-stage synthetic steps for the target molecules as well as the results of the detailed mouse immunization studies and the molecular-level mechanistic investigations, the final outcome of this project after the next grant period, in terms of synthetic access to potent lead compounds as well as key insights into saponin mechanisms of immunopotentiation, is anticipated to go beyond the state-of-the-art. The final results are expected to be significant and ground-breaking, enabling the development of new immunotherapeutic drugs and synthetic vaccines and pushing the frontiers of knowledge in adjuvant and vaccine research.