Pritzker School of Molecular Engineering
Published July 3, 2024 | Version v1
Journal article Open

From hit to vial: Precision discovery and development of an imidazopyrimidine TLR7/8 agonist adjuvant formulation

Creators

  • 1. Boston Children's Hospital
  • 2. Harvard University
  • 3. The Scripps Research Institute
  • 4. Access to Advanced Health Institute
  • 5. University of Chicago

Description

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)–activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

Contingent on scientific review and a fully executed material transfer agreement with Boston Children's Hospital Technology & Innovation Development Office, PVP-037 (analogs and formulations) and/or access to the broader "PVP Adjuvant Portfolio," will be provided by the PVP team upon request as submitted to D.J.D. or O.L. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

Files

sciadv.adg3747.pdf

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Additional details

Identifiers

DOI
10.1126/sciadv.adg3747
Other
oai:uchicago.tind.io:12883

Funding

National Institutes of Allergy and Infectious Diseases
HHSN272201400052C
National Institutes of Allergy and Infectious Diseases
HHSN272201800047C
National Institutes of Allergy and Infectious Diseases
75N93019C00044
National Institute of Allergy and Infectious Diseases
1R21AI137932-01A1
Boston Children's Hospital
Department of Pediatrics and the Chief Scientific Office
National Institutes of Health
1 S10OD030332-01

UChicago Information

Division(s)
Pritzker School of Molecular Engineering