6″-Modifed α-GalCer-peptide conjugate vaccine candidates protect against liver-stage malaria

Meijlink, Michael A; Chua, Yu Cheng; Chan, Susanna T. S.; Anderson, Regan J.; Rosenberg, Matthew W; Cozijnsen, Anton; Mollard, Vanessa; McFadden, Geoffrey I.; Draper, Sarah; Holz, Lauren E.; Hermans, Ian F.; Heath, William R.; Painter, Gavin F.; Compton, Benjamin J.

doi:10.1039/d1cb00251a

Cited by 11 publications

(16 citation statements)

References 42 publications

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“…Oxime ligation between carbonyl-containing compounds (i.e., aldehydes or ketones) and peptides functionalized with an aminooxy group is a proven way to efficiently generate glycolipid-peptide conjugate vaccines. ,, Conditions promoting oxime bond formation include the use of aniline catalysts under mildly acidic conditions (∼pH 3–5) . To investigate this ligation approach, the corresponding G0 vaccine construct was synthesized whereby α-GalCer amine 5 was reacted with the activated ester of 8-oxo-nonanoic acid ( 23 ) to give α-GalCer ketone 24 (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…To investigate this ligation approach, the corresponding G0 vaccine construct was synthesized whereby α-GalCer amine 5 was reacted with the activated ester of 8-oxo-nonanoic acid ( 23 ) to give α-GalCer ketone 24 (Scheme ). Having previously shown that a solution of aniline and TFA in hexafluoroisopropanol (HFIP) can efficiently catalyze the oxime ligation of an appropriately functionalized glycolipid and peptide, these reaction conditions were examined for synthesis of the G0 vaccine (Scheme ). Starting with ketone 24 and aminooxy acetyl (AoA)-FFRKRAHYNIVTF ( 25 ), a series of concentrations of aniline (100, 200, and 400 mM) in HFIP were assessed for the synthesis of the G0 1:1 conjugate ( 26 ).…”

Section: Resultsmentioning

confidence: 99%

“…The capacity of α-GalCer to adjuvant synthetic peptide-based vaccines in various disease models including cancer − and infectious disease − has been enhanced by strategies that encourage presentation of α-GalCer and peptide by the same APC. ,− This includes encapsulation into a variety of different synthetic vaccine particles, − employing filamentous bacteriophages or virus-like particles, and attachment to gold nanoparticles . Although these strategies to promote codelivery have proven effective in animal models, controlling and quantifying the ratio of adjuvant and antigen in these approaches is challenging.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Peptide-Adjuvant Conjugate Vaccines with Increasing Antigen Content

et al. 2023

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Synthetic vaccines that induce T cell responses to peptide epitopes are a promising immunotherapy for both communicable and noncommunicable diseases. Stimulating strong and sustained T cell responses requires antigen delivery to appropriately activated antigen presenting cells (APCs). One way this can be accomplished is by chemically conjugating immunogenic peptide epitopes with α-galactosylceramide (α-GalCer), a glycolipid that acts as an immune adjuvant by inducing stimulatory interactions between APCs and type I natural killer T (NKT) cells. Here we investigate whether increasing the ratio of antigen:adjuvant improves antigen-specific T cell responses. A series of conjugate vaccines was prepared in which one, two, four, or eight copies of an immunogenic peptide were covalently attached to a modified form of α-GalCer via the poly(ethoxyethylglycinamide) dendron scaffold. Initial attempts to synthesize these multivalent conjugate vaccines involved attaching the bicyclo[6.1.0]non-4-yne (BCN) group to the adjuvant-dendron structure followed by strain-promoted azide–alkyne cycloaddition of the peptide. Although this approach was successful for preparing vaccines with either one or two peptide copies, the synthesis of vaccines requiring attachment of four or eight BCN groups suffered from low yields due to cyclooctyne degradation. Instead, conjugate vaccines containing up to eight peptide copies were readily achieved through oxime ligation with adjuvant-dendron constructs decorated with the 8-oxo-nonanoyl group. When evaluating T cell responses to vaccination in mice, we confirmed a significant advantage to conjugation over admixes of peptide and α-GalCer, regardless of the peptide to adjuvant ratio, but there was no advantage to increasing the number of peptides attached. However, it was notable that the higher ratio conjugate vaccines required lower levels of NKT cell activation to be effective, which could be a safety advantage for future vaccine candidates.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Peptide-Adjuvant Conjugate Vaccines with Increasing Antigen Content

et al. 2023

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“…Indeed, the use of synthetic peptides chemically conjugated to immunostimulating lipids, such as a prodrug form of α-GalCer or its derivatives, showed the promising potential of the combined use of iNKT and T cell antigens to increase immune responses in different pathological conditions such as malaria [ 44 ], allergies [ 45 ], and hematopoietic [ 46 ] and solid tumors [ 20 , 47 ]. Moreover, α-GalCer-peptide administration further demonstrated the efficacy of the simultaneous co-delivery of iNKT and T cell antigens compared to the use of free α-GalCer, suggesting the importance of releasing both components within the same antigen-presenting cell, for the iNKT-mediated stimulation of antigen-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

Co-Delivery of the Human NY-ESO-1 Tumor-Associated Antigen and Alpha-GalactosylCeramide by Filamentous Bacteriophages Strongly Enhances the Expansion of Tumor-Specific CD8+ T Cells

Manco

D’Apice

Trovato

et al. 2023

Viruses

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Tumor-associated antigens (TAAs) represent attractive targets in the development of anti-cancer vaccines. The filamentous bacteriophage is a safe and versatile delivery nanosystem, and recombinant bacteriophages expressing TAA-derived peptides at a high density on the viral coat proteins improve TAA immunogenicity, triggering effective in vivo anti-tumor responses. To enhance the efficacy of the bacteriophage as an anti-tumor vaccine, we designed and generated phage particles expressing a CD8+ peptide derived from the human cancer germline antigen NY-ESO-1 decorated with the immunologically active lipid alpha-GalactosylCeramide (α-GalCer), a potent activator of invariant natural killer T (iNKT) cells. The immune response to phage expressing the human TAA NY-ESO-1 and delivering α-GalCer, namely fdNY-ESO-1/α-GalCer, was analyzed either in vitro or in vivo, using an HLA-A2 transgenic mouse model (HHK). By using NY-ESO-1-specific TCR-engineered T cells and iNKT hybridoma cells, we observed the efficacy of the fdNY-ESO-1/α-GalCer co-delivery strategy at inducing activation of both the cell subsets. Moreover, in vivo administration of fdNY-ESO-1 decorated with α-GalCer lipid in the absence of adjuvants strongly enhances the expansion of NY-ESO-1-specific CD8+ T cells in HHK mice. In conclusion, the filamentous bacteriophage delivering TAA-derived peptides and the α-GalCer lipid may represent a novel and promising anti-tumor vaccination strategy.

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“…The OH at C-6 of the galactose is the only hydroxyl group not involved in hydrogen bonding in the ternary complex between the glycolipid, the CD1d protein and the T-cell receptor (TCR) of iNKT cells, [22] thus it has been the most common site chosen for functionalization en route to immunogenic α-GalCer conjugates. [19,20,23] Herein we open a new diversification hot-spot at a position that has not been previously derivatized, namely the amide bond connecting the phytosphingosine base and the fatty acid. For this purpose, we introduce a multicomponent reaction (MCR) approach that enables the onepot construction of a parallel library of α-GalCer derivatives featuring two different diversification sites.…”

Section: Introductionmentioning

confidence: 99%

Diversification of a Novel α‐Galactosyl Ceramide Hotspot Boosts the Adjuvant Properties in Parenteral and Mucosal Vaccines

Méndez,

Vasco,

Ebensen

et al. 2023

Angew Chem Int Ed

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The development of potent adjuvants is an important step for improving the performance of subunit vaccines. CD1d agonists, such as the prototypical α‐galactosyl ceramide (α‐GalCer), are of special interest due to their ability to activate iNKT cells and trigger rapid dendritic cell maturation and B‐cell activation. Here, we introduce a novel derivatization hotspot at the α‐GalCer skeleton, namely the N‐substituent at the amide bond. The multicomponent diversification of this previously unexplored glycolipid chemotype space permitted the introduction of a variety of extra functionalities that can either potentiate the adjuvant properties or serve as handles for further conjugation to antigens toward the development of self‐adjuvanting vaccines. This strategy led to the discovery of compounds eliciting enhanced antigen‐specific T cell stimulation and a higher antibody response when delivered either by parenteral or mucosal route, compared to a known potent CD1d agonist. Notably, various functionalized α‐GalCer analogs showed a more potent adjuvant effect after intranasal immunization than a PEGylated α‐GalCer analog previously optimized for this purpose. Ultimately, this work could open multiple avenues of opportunity for the use of mucosal vaccines against microbial infections.

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6″-Modifed α-GalCer-peptide conjugate vaccine candidates protect against liver-stage malaria

Abstract: Self-adjuvanting vaccines consisting of peptide epitopes conjugated to immune adjuvants are a powerful way of generating antigen-specific immune responses. We previously showed that a Plasmodium-derived peptide conjugated to a rearranged...

Cited by 11 publications

References 42 publications

Synthesis and Biological Evaluation of Peptide-Adjuvant Conjugate Vaccines with Increasing Antigen Content

Synthesis and Biological Evaluation of Peptide-Adjuvant Conjugate Vaccines with Increasing Antigen Content

Co-Delivery of the Human NY-ESO-1 Tumor-Associated Antigen and Alpha-GalactosylCeramide by Filamentous Bacteriophages Strongly Enhances the Expansion of Tumor-Specific CD8+ T Cells

Diversification of a Novel α‐Galactosyl Ceramide Hotspot Boosts the Adjuvant Properties in Parenteral and Mucosal Vaccines

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