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Better Adjuvant Honors Lost Colleague

Vaccines: Simplified version of promising immunity-boosting agent is less toxic, easier to make

by Stu Borman
June 5, 2014 | A version of this story appeared in Volume 92, Issue 23

A line structure of a QS-21 analog.
Chemists stripped QS-21 down to this analog. The changes included deleting four sugars, replacing an aldehyde with a methyl group, and simplifying the acyl chain (top right).

For years, the late chemist David Y. Gin’s group at Memorial Sloan Kettering Cancer Center (MSKCC) has been trying to develop simplified and enhanced versions of the promising immune-boosting agent QS-21. They have sought to ease its synthesis, improve its properties, and learn more about how it works.

The group, adopted by MSKCC’s Derek S. Tan after Gin’s death in 2011 at age 43, has now made significant progress toward those goals.

QS-21 is a natural-product “adjuvant,” an agent co-administered with vaccines to make them work better. It’s one of the most potent adjuvants known and has been tested in dozens of human clinical trials. It could soon be commercialized as part of a malaria vaccine being developed by GlaxoSmithKline. But it is unstable, has some toxicity, and is isolated as a mixture of two isomers from tree bark in low yields and therefore in limited supply.

Now, the Gin/Tan group and those of Philip O. Livingston, Govind Ragupathi, and Jason S. Lewis at MSKCC have created a greatly simplified QS-21 analog that is more synthetically accessible and less toxic than the natural product (Nat. Chem. 2014, DOI: 10.1038/nchem.1963). They have also uncovered new details on QS-21’s poorly understood mechanism of action.

The team plans to commercialize such semisynthetic QS-21 variants as adjuvants through Adjuvance Technologies, a company Gin started with Livingston and Ragupathi.

The researchers created the analog from QS-21 by deleting a branched trisaccharide and an additional sugar and simplifying an acyl chain, among other structural changes. The analog retains QS-21’s full activity while lowering its toxicity.

“I would never have expected that one could strip down this beast of a molecule to this extent and still retain activity, much less have reduced toxicity,” comments Jeffrey C. Gildersleeve, head of chemical glycobiology at the National Cancer Institute and winner of the ACS Division of Carbohydrate Chemistry’s 2011 David Y. Gin New Investigator Award.

The researchers also found that an aldehyde group in QS-21’s triterpene domain is not required for activity. Previous studies had proposed that the aldehyde helps stimulate immune-cell activation by reacting with cell-surface targets to form a Schiff base. But in the analog, it has been replaced with just a methyl group, calling the earlier proposals into question.

Introducing an aryl iodide into the acyl chain domain enabled the researchers to use radioiodinated versions to study the analog’s in vivo biodistribution. These studies revealed that active QS-21 variants accumulate in draining lymph nodes, sites of immune-cell maturation, but inactive ones don’t—suggesting that active variants help direct antigen-presenting cells to lymph nodes for presentation of antigens to the immune system. By looking in this way “at how the localization and distribution of the adjuvant correlates with its immunogenicity,” the study allows researchers to get a better handle on its mechanism, says vaccine-mechanism specialist Gregory Mullen of King’s College London, who has worked with QS-21.


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