Carrier diversity and chemical ligations in the toolbox for designing tumor-associated carbohydrate antigens (TACAs) as synthetic vaccine candidates

Roy, René; Mousavifar, Leila

doi:10.1039/d2cs01032a

Cited by 5 publications

(2 citation statements)

References 233 publications

(467 reference statements)

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“…As adaptive immune responses are critical for cancer immunotherapy and are primarily initiated through the accumulation of the conjugate vaccine at the secondary lymphoid organs, such as LN, spleen, and gut mucosal-associated lymphoid tissues, accumulating conjugate vaccine at the secondary lymphoid organs improves its immunogenicity. [24,25] The synergy of albumin-based drug delivery, along with its excellent cargo capabilities, contributes to the advancements in cancer immunotherapy. Vaccines incorporated with TACA and appropriate molecular components demonstrate efficacies in enhancing immune activation pathways.…”

Section: Introductionmentioning

confidence: 99%

Lymph Node Targeting Mediated by Albumin Hitchhiking of Synthetic Tn Glycolipid Leads to Robust In Vivo Antibody Production

Thekke Veettil,

Jayaraman

2024

Adv Healthcare Materials

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Tn antigen is a tumor‐associated carbohydrate antigen (TACA), which is present prominently on the tumor cell surfaces and attracts an interest in the vaccine development. In this work, we demonstrate that a synthetic Tn antigen carrying glycoconjugate forms complex with circulating albumin, delivers the antigen to lymph nodes and leads to efficient production of antibody against the antigen. Synthetic Tn antigen glycoconjugate, possessing DSPE‐PEG2000 linker and lipophilic moieties, undergoes micellization in PBS buffer. In the presence of bovine serum albumin (BSA), demicellization of the glycolipid occurs, with rate a constant of 0.18 min−1. In vitro studies show that the glycoconjugate binds preferentially to BSA in the presence of cells. Immunological assessments in mice models reveal the albumin‐enabled delivery of the Tn glycoconjugate to antigen presenting cells in the lymph nodes specifically, leading to a robust humoral immune response. ELISA titres show superior binding, with a saturation dilution of 1:51200 for Tn glycoconjugate, in comparison to that mediated by the Tn‐BSA covalent conjugate with a saturation dilution of 1:6400. Immunohistochemical staining shows delivery of Tn glycoconjugate at the lymph nodes, specifically at the subcapsular sinus and interfollicular areas. The work highlights the potential of albumin‐mediated target delivery strategy for cancer immunotherapies.This article is protected by copyright. All rights reserved

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Section: Introductionmentioning

confidence: 99%

Lymph Node Targeting Mediated by Albumin Hitchhiking of Synthetic Tn Glycolipid Leads to Robust In Vivo Antibody Production

Thekke Veettil,

Jayaraman

2024

Adv Healthcare Materials

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“…MUC1-based vaccine candidates typically contain the full sequence of MUC1 glycosylated at one or multiple positions with Tn or other TACAs. , Despite the synthetic efforts, − there have been no successful clinical applications to date, which may be a result of the atypical glycosylated proteinsthat express some of these antigensbeing exposed on healthy cells at low concentrations, which may lead to tolerance induction and, consequently, poor immune response in mice . Our research group and others have been working to overcome this issue by using artificial MUC1 derivatives designed in the lab. − These synthetic glycopeptides promise to be more immunogenic and consequently stimulate an effective anti-MUC1 response, as well as being resistant to enzymatic degradation .…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses

Bermejo,

Guerreiro,

Eguskiza

et al. 2023

JACS Au

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glycopeptides are exceptional candidates for potential cancer vaccines. However, their autoantigenic nature often results in a weak immune response. To overcome this drawback, we carefully engineered synthetic antigens with precise chemical modifications. To be effective and stimulate an anti-MUC1 response, artificial antigens must mimic the conformational dynamics of natural antigens in solution and have an equivalent or higher binding affinity to anti-MUC1 antibodies than their natural counterparts. As a proof of concept, we have developed a glycopeptide that contains noncanonical amino acid (2S,3R)-3-hydroxynorvaline. The unnatural antigen fulfills these two properties and effectively mimics the threonine-derived antigen. On the one hand, conformational analysis in water shows that this surrogate explores a landscape similar to that of the natural variant. On the other hand, the presence of an additional methylene group in the side chain of this analog compared to the threonine residue enhances a CH/π interaction in the antigen/antibody complex. Despite an enthalpy−entropy balance, this synthetic glycopeptide has a binding affinity slightly higher than that of its natural counterpart. When conjugated with gold nanoparticles, the vaccine candidate stimulates the formation of specific anti-MUC1 IgG antibodies in mice and shows efficacy comparable to that of the natural derivative. The antibodies also exhibit cross-reactivity to selectively target, for example, human breast cancer cells. This investigation relied on numerous analytical (e.g., NMR spectroscopy and X-ray crystallography) and biophysical techniques and molecular dynamics simulations to characterize the antigen−antibody interactions. This workflow streamlines the synthetic process, saves time, and reduces the need for extensive, animal-intensive immunization procedures. These advances underscore the promise of structure-based rational design in the advance of cancer vaccine development.

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Ganglioside GM3-based anticancer vaccines: Reviewing the mechanism and current strategies

Zhang,

Terreni,

Liu

et al. 2024

Biomedicine & Pharmacotherapy

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Carrier diversity and chemical ligations in the toolbox for designing tumor-associated carbohydrate antigens (TACAs) as synthetic vaccine candidates

Abstract: This review highlights the recent development in the use of carriers of increasing simplicities and versatile chemical ligation processes leading to synthetic vaccine candidates against tumor-associated carbohydrate antigens (TACAs).

Cited by 5 publications

References 233 publications

Lymph Node Targeting Mediated by Albumin Hitchhiking of Synthetic Tn Glycolipid Leads to Robust In Vivo Antibody Production

Lymph Node Targeting Mediated by Albumin Hitchhiking of Synthetic Tn Glycolipid Leads to Robust In Vivo Antibody Production

Structure-Guided Approach for the Development of MUC1-Glycopeptide-Based Cancer Vaccines with Predictable Responses

Ganglioside GM3-based anticancer vaccines: Reviewing the mechanism and current strategies

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