Design of Fully Synthetic, Self-Adjuvanting Vaccine Incorporating the Tumor-Associated Carbohydrate Tn Antigen and Lipoamino Acid-Based Toll-like Receptor 2 Ligand

Abdel–Aal, Abu-Baker M.; Elnaggar, Dina H.; Zaman, Mehfuz; Batzloff, Michael R.; Tóth, István

doi:10.1021/jm300822g

Cited by 38 publications

(36 citation statements)

References 25 publications

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“…Constructs incorporating a cluster of the most common tumor-associated carbohydrate antigens (known as Tn antigen) covalently attached to T cell peptide epitopes and LAA consisting of two 16-carbon lipoamino acids have been evaluated (108). These constructs induced potent antibody responses in mice without the need for an additional adjuvant, carrier protein, or special formulation (e.g., liposomes).…”

Section: Lipoamino Acidmentioning

confidence: 99%

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Immunostimulation by Synthetic Lipopeptide-Based Vaccine Candidates: Structure-Activity Relationships

Zaman¹,

Tóth²

2013

Front. Immunol.

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Peptide-based vaccines offer several advantages over conventional whole organism or protein approaches by offering improved purity and specificity in inducing immune response. However, peptides alone are generally non-immunogenic. Concerns remain about the toxicity of adjuvants which are critical for immunogenicity of synthetic peptides. The use of lipopeptides in peptide vaccines is currently under intensive investigation because potent immune responses can be generated without the use of adjuvant (thus are self-adjuvanting). Several lipopeptides derived from microbial origin, and their synthetic versions or simpler fatty acid moieties impart this self-adjuvanting activity by signaling via Toll-like receptor 2 (TLR2). Engagement of this innate immune receptor on antigen-presenting cell leads to the initiation and development of potent immune responses. Therefore optimization of lipopeptides to enhance TLR2-mediated activation is a promising strategy for vaccine development. Considerable structure-activity relationships that determine TLR2 binding and consequent stimulation of innate immune responses have been investigated for a range of lipopeptides. In this mini review we address the development of lipopeptide vaccines, mechanism of TLR2 recognition, and immune activation. An overview is provided of the best studied lipopeptide vaccine systems.

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Section: Lipoamino Acidmentioning

confidence: 99%

“…These constructs induced potent antibody responses in mice without the need for an additional adjuvant, carrier protein, or special formulation (e.g., liposomes). Structure-activity studies demonstrated that linear or branched vaccine architecture had a significant effect on antibody recognition (108). …”

Section: Lipoamino Acidmentioning

confidence: 99%

Immunostimulation by Synthetic Lipopeptide-Based Vaccine Candidates: Structure-Activity Relationships

Zaman¹,

Tóth²

2013

Front. Immunol.

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“…For example, Pam3CSK4 enhanced CD8 + regulatory T cell (T reg ) survival (105). Interestingly, glycolipopeptide constructs can be used to design composite tumor vaccines (106). These compounds contain carbohydrate antigens, CD4 + or CD8 + T cell epitopes, and TLR2 stimulating lipid chains.…”

Section: Therapeutic Potential Of Tlr2 Signaling Plasticitymentioning

confidence: 99%

Evolving Bacterial Envelopes and Plasticity of TLR2-Dependent Responses: Basic Research and Translational Opportunities

Lee

Madrenas

2013

Front. Immunol.

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Innate immune mechanisms that follow early recognition of microbes influence the nature and magnitude of subsequent adaptive immune responses. Early detection of microbes depends on pattern recognition receptors that sense pathogen-associated molecular patterns or microbial-associated molecular patterns (PAMPS or MAMPs, respectively). The bacterial envelope contains MAMPs that include membrane proteins, lipopeptides, glycopolymers, and other pro-inflammatory molecules. Bacteria are selected by environmental pressures resulting in quantitative or qualitative changes in their envelope structures that often promote evasion of host immune responses and therefore, infection. However, recent studies have shown that slight, adaptive changes in MAMPs on the bacterial cell wall may result in their ability to induce the secretion not only of pro-inflammatory cytokines but also of anti-inflammatory cytokines. This effect can fine-tune the subsequent response to microbes expressing these MAMPs and lead to the establishment of a commensal state within the host rather than infectious disease. In this review, we will examine the plasticity of Toll-like receptor (TLR) 2 signaling as evidence of evolving MAMPs, using the better-characterized TLR4 as a template. We will review the role of differential dimerization of TLR2 and the arrangement of signaling complexes and co-receptors in determining the capacity of the host to recognize an array of TLR2 ligands and generate different immune responses to these ligands. Last, we will assess briefly how this plasticity may expand the array of interactions between microbes and immune systems beyond the traditional disease-causing paradigm.

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“…[36] The development of less toxic adju-vants and self-adjuvanting multi-componentv accines has also been investigated,r esulting in remarkable immunological effects. [37][38][39][40][41][42][43][44][45] Finally,w hen many structures only present the carbohydrate moiety of the TACA instead of the native glycopeptide antigen, more relevant results have been obtained compared to when the TACA are linked to an amino acid of the native peptide fragment. [30,[46][47][48] However,d espite thesei mportant improvements, no carbohydrate-based antitumor synthetic vaccine has succeeded in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Heterovalent Glycodendrimers as Epitope Carriers for Antitumor Synthetic Vaccines

Pifferi

Thomas

Goyard

et al. 2017

Chemistry A European J

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The large majority of TACA‐based (TACA=Tumor‐Associated Carbohydrate Antigens) antitumor vaccines target only one carbohydrate antigen, thereby often resulting in the incomplete destruction of cancer cells. However, the morphological heterogeneity of the tumor glycocalix, which is in constant evolution during malignant transformation, is a crucial point to consider in the design of vaccine candidates. In this paper, an efficient synthetic strategy based on orthogonal chemoselective ligations to prepare fully synthetic glycosylated cyclopeptide scaffolds grafted with both Tn and TF antigen analogues is reported. To evaluate their ability to be recognized as tumor antigens, direct interaction ELISA assays have been performed with the anti‐Tn monoclonal antibody 9A7. Although both heterovalent structures showed binding capacities with 9A7, the presence of the second TF epitope did not interfere with the recognition of Tn except in one epitope arrangement. This heterovalent glycosylated structure thus represents an attractive epitope carrier to be further functionalized with T‐cell peptide epitopes.

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Design of Fully Synthetic, Self-Adjuvanting Vaccine Incorporating the Tumor-Associated Carbohydrate Tn Antigen and Lipoamino Acid-Based Toll-like Receptor 2 Ligand

Cited by 38 publications

References 25 publications

Immunostimulation by Synthetic Lipopeptide-Based Vaccine Candidates: Structure-Activity Relationships

Immunostimulation by Synthetic Lipopeptide-Based Vaccine Candidates: Structure-Activity Relationships

Evolving Bacterial Envelopes and Plasticity of TLR2-Dependent Responses: Basic Research and Translational Opportunities

Heterovalent Glycodendrimers as Epitope Carriers for Antitumor Synthetic Vaccines

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