QS-21

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Basic structure of QS-21, consisting of a quillaic acid triterpene (black) substituted with a branched trisaccharide (blue) and a linear tetrasaccharide (green), which is in turn connected to an acyl chain (red) via a hydrolytically labile ester. QS-21 is a 65:35 mixture of the Apiose- and the Xylose-substituted variants of above molecule. QS-21.svg
Basic structure of QS-21, consisting of a quillaic acid triterpene (black) substituted with a branched trisaccharide (blue) and a linear tetrasaccharide (green), which is in turn connected to an acyl chain (red) via a hydrolytically labile ester. QS-21 is a 65:35 mixture of the Apiose- and the Xylose-substituted variants of above molecule.

QS-21 is a purified plant extract used as a vaccine adjuvant. It is derived from the soap bark tree (Quillaja saponaria), which is native to the countries of Chile, Peru, and Bolivia. [1] The crude drug (Quillajae cortex, Quillaia) is imported from Peru and Chile. [2]

Contents

The extract contains water-soluble triterpene glycosides, which are members of a family of plant-based compounds called saponins. It has been tested as an adjuvant in various vaccines in attempts to improve their efficacy. It is believed to enhance both humoral and cell-mediated immunity. [1]

Use

QS-21 has been clinically evaluated as a vaccine adjuvant. As of 2002, it had been tested in more than 3000 patients in 60 clinical trials.

Direct, unencapsuled QS-21 is very liable to hydrolysis. It also causes immediate pain at injection site and in vitro causes hemolysis. All of these can be prevented by packaging QS-21 into lipid-based particles, which also have the added advantage of targeting its delivery to phagocytes. It is part of: [3]

Sources

Tree bark

Isolation of QS-21 destroys the soap bark tree, prompting governments to regulate industrial extraction. [1] The United States has invoked the 1950 Defense Production Act to preserve vaccine raw materials for its own companies. [7]

A semi-synthesis strategy from 2013 relies on purifying the prosapogenin (triterpene and branched trisaccharide) part of the molecule and adding the rest of QS-21 synthetically, doubling the yield over simple isolation (amount produced from a given amount of tree bark). This semi-synthetic approach has also facilitated experimentation with alternative acyl chain compositions. [8]

In 2017, FDA approved the Shingrix vaccine which makes use of the extracted form of QS-21 made by Agenus under the trade name Stimulon. [9] Agenus remains the sole US manufacturer of FDA-approved QS-21 as of 2021. [10]

Sustainable biomass pruning

Saponins, including QS-21, are present throughout the biomass of Quillaja saponaria Mol., though typically at lower concentrations in the branches, trunk, and leaves compared to the bark. However, these non-bark components represent a significantly larger biomass volume and thus contribute a higher total yield of saponins. [11] The practice of pruning Quillaja trees to harvest this biomass for saponin extraction has been used sustainably by the food industry since 2000. [12] In 2022, the company Q-Vant communicated having achieved the fractioning of QS-21 from any part of the Quillaja plant, including branches and trunks obtained through renewable pruning methods. [13]

Plant tissue culture

Several companies have succeeded in isolating the compound from plant tissue cultures of the soapbark plant.

The aforementioned Agenus created a spin-off company called SaponiQx to manage its QS-21 business. SaponiQx submitted the Master File for its cultured plant cell (cpc) version of QS-21 to the US FDA in 2023. [14] An animal study using this cpc-QS-21 was published in 2024. [15]

Transgenic tobacco

In 2024, a team at the John Innes Centre in Norwich, UK identified the complete 20-step biosynthetic pathway of QS-21 and cloned it into tobacco. [16]

Transgenic yeast

In 2024, an international team of collaborators succeed in engineering yeast to perform the complete biosynthesis of QS-21. [17] One of the scientists pointed out that the yeast process is around 1000 times faster than trees because only mature trees produce QS-21. "Even at the levels we're producing it, it's cheaper than producing it from the plant." [17]

Total synthesis

QS-21 has been made by total chemical synthesis, but required an inefficient 76-step process that is not commercially viable. This is not unlike the total chemical synthesis of many other complex biomolecules, which served mainly to confirm their structure rather than to produce an economically-viable source. [17]

References

  1. 1 2 3 Ragupathi G, Gardner JR, Livingston PO, Gin DY (2013). "Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer". Expert Rev Vaccines. 10 (4): 463–70. doi:10.1586/erv.11.18. PMC   3658151 . PMID   21506644.
  2. ↑ Max Wichtl, ed. (2004). Herbal Drugs and Phytopharmaceuticals: A Handbook for Practice on a Scientific Basis. Medpharm Publishers. p. 492. ISBN 3-88763-100-5.
  3. 1 2 3 4 5 Stertman, L; Palm, AE; Zarnegar, B; Carow, B; Lunderius Andersson, C; Magnusson, SE; Carnrot, C; Shinde, V; Smith, G; Glenn, G; Fries, L; Lövgren Bengtsson, K (31 December 2023). "The Matrix-M™ adjuvant: A critical component of vaccines for the 21(st) century". Human Vaccines & Immunotherapeutics. 19 (1): 2189885. doi:10.1080/21645515.2023.2189885. PMC   10158541 . PMID   37113023. The Matrix-M adjuvant consists of two different populations of physically stable nanoparticles mixed at a defined ratio (85% Matrix-A + 15% Matrix-C). Matrix-A and Matrix-C contain different Q. saponaria saponin fractions with complementary properties. Matrix-C particles contain Fraction-C saponins (mainly consisting of QS-21)...
  4. ↑ "SHINGRIX package insert" (PDF). Food and Drug Administration. Archived from the original (PDF) on November 5, 2017. Retrieved 7 April 2019.
  5. ↑ Alving, Carl R.; Peachman, Kristina K.; Matyas, Gary R.; Rao, Mangala; Beck, Zoltan (3 March 2020). "Army Liposome Formulation (ALF) family of vaccine adjuvants". Expert Review of Vaccines. 19 (3): 279–292. doi:10.1080/14760584.2020.1745636. PMC   7412170 . PMID   32228108.
  6. ↑ Alving, Carl R.; BECK, Zoltan (8 October 2019). "US10434167B2 Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin".
  7. ↑ Wang P (March 2021). "Natural and Synthetic Saponins as Vaccine Adjuvants". Vaccines. 9 (3): 222. doi: 10.3390/vaccines9030222 . PMC   8001307 . PMID   33807582.
  8. ↑ Chea EK, Fernández-Tejada A, Damani P, Adams MM, Gardner JR, Livingston PO, Ragupathi G, Gin DY (2013). "Synthesis and preclinical evaluation of QS-21 variants leading to simplified vaccine adjuvants and mechanistic probes". J Am Chem Soc. 134 (32): 13448–57. doi:10.1021/ja305121q. PMC   3436428 . PMID   22866694.
  9. ↑ "FDA Approves GSK's Shingles Vaccine with Agenus' QS-21 Stimulon® Adjuvant" (Press release).
  10. ↑ Agenus Inc. "First QS-21 Royalty Payment Due to Agenus is Triggered". www.prnewswire.com (Press release).
  11. ↑ Instituto Forestal (Santiago, Chile); Instituto de Desarrollo Agropecuario (Chile); Fundación para la Innovación Agraria (Chile), eds. (2000). Monografía de Quillay, Quillaja saponaria (1. ed.). Santiago, Chile?: INFOR : FIA : INDAP. ISBN   978-956-7727-48-3.
  12. ↑ Martín, Ricardo San; Briones, Reinaldo (July 1999). "Industrial uses and sustainable supply ofQuillaja saponaria (Rosaceae) saponins". Economic Botany. 53 (3): 302–311. Bibcode:1999EcBot..53..302M. doi:10.1007/BF02866642. ISSN   0013-0001.
  13. ↑ Marino, Dan (2022-01-12). "Q-VANT Biosciences Launches to Solve the Pharmaceutical Industry Problem of Limited Quillaja Saponin-Based Adjuvants for Life-Saving Vaccines". Drug Development and Delivery. Retrieved 2025-07-04.
  14. ↑ "SaponiQx Announces Breakthrough in Scaling Up of STIMULON™ Cultured Plant Cell Adjuvant".
  15. ↑ Swart, Maarten; Allen, Jessica; Reed, Brendan; Izquierdo Gil, Ana; Verspuij, Johan; Schmit-Tillemans, Sonja; Chakkumkal, Anish; Findeis, Mark; Hafner, Angela V.; Harjivan, Chandresh; Kurnat, Rebecca; Kuipers, Harmjan; Zahn, Roland; Brandenburg, Boerries (20 December 2024). "Plant Cell Culture-Derived Saponin Adjuvant Enhances Immune Response Against a Stabilized Human Metapneumovirus Pre-Fusion Vaccine Candidate". Vaccines. 12 (12): 1435. doi: 10.3390/vaccines12121435 . PMC   11728754 . PMID   39772095.
  16. ↑ Martin LB, Kikuchi S, Rejzek M, Owen C, Reed J, Orme A, Misra RC, El-Demerdash A, Hill L, Hodgson H, Liu Y, Keasling JD, Field RA, Truman AW, Osbourn A (April 2024). "Complete biosynthesis of the potent vaccine adjuvant QS-21". Nat Chem Biol. 20 (4): 493–502. doi:10.1038/s41589-023-01538-5. PMC   10972754 . PMID   38278997.
  17. 1 2 3 Liu Y, Zhao X, Gan F, Chen X, Deng K, Crowe SA, Hudson GA, Belcher MS, Schmidt M, Astolfi MC, Kosina SM, Pang B, Shao M, Yin J, Sirirungruang S, Iavarone AT, Reed J, Martin LB, El-Demerdash A, Kikuchi S, Misra RC, Liang X, Cronce MJ, Chen X, Zhan C, Kakumanu R, Baidoo EE, Chen Y, Petzold CJ, Northen TR, Osbourn A, Scheller H, Keasling JD (May 2024). "Complete biosynthesis of QS-21 in engineered yeast". Nature. 629 (8013): 937–944. Bibcode:2024Natur.629..937L. doi:10.1038/s41586-024-07345-9. PMC   11111400 . PMID   38720067.
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