Immunomodulatory regulation by heat-labile enterotoxins and potential therapeutic applications

Knapp, Mary-Peyton A.; Johnson, Taylor A.; Ritter, Madison K.; Rainer, Robert; Fiester, Steven E.; Grier, Jennifer T.; Connell, Terry D.; Arce, Sergio

doi:10.1080/14760584.2021.1945449

Cited by 3 publications

(3 citation statements)

References 99 publications

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“…The immunogenicity observed for the LTp50-based vaccine formulation is attributed to the adjuvant activity exerted by the LTB used as a built-in adjuvant and the action of alum as a particulate adjuvant. Since LTB binds specifically to GM1 receptors present in many cell types, it can stimulate immune responses via signal transduction events related to the proliferation of T-cells, an increase in cytokine release, an augment in mucosal/systemic antibody responses, and enhancement of antigen-presenting cells [ 48 ]; it also induces B and T cells clustering and delays/arrests T-cell division following endocytosis or B-cell receptor (BCR) uptake of antigen in a ganglioside-mediated manner [ 49 ]. LTB has been used as a protein partner (built-in adjuvant) in oral and injectable vaccines.…”

Section: Discussionmentioning

confidence: 99%

Production and Immunogenicity Assessment of LTp50: An Escherichia coli-Made Chimeric Antigen Targeting S1- and S2-Epitopes from the SARS-CoV-2/BA.5 Spike Protein

Wong-Arce,

Gonzalez-Ortega,

Romero-Maldonado

et al. 2024

Pharmaceuticals

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Subunit vaccines stand as a leading approach to expanding the current portfolio of vaccines to fight against COVID-19, seeking not only to lower costs but to achieve long-term immunity against variants of concern and have the main attributes that could overcome the limitations of the current vaccines. Herein a chimeric protein targeting S1 and S2 epitopes, called LTp50, was designed as a convenient approach to induce humoral responses against SARS-CoV-2. LTp50 was produced in recombinant Escherichia coli using a conventional pET vector, recovering the expected antigen in the insoluble fraction. LTp50 was purified by chromatography (purity > 90%). The solubilization and refolding stages helped to obtain a stable protein amenable for vaccine formulation. LTp50 was adsorbed onto alum, resulting in a stable formulation whose immunogenic properties were assessed in BALB/c mice. Significant humoral responses against the S protein (BA.5 variant) were detected in mice subjected to three subcutaneous doses (10 µg) of the LTp50/alum formulation. This study opens the path for the vaccine formulation optimization using additional adjuvants to advance in the development of a highly effective anti-COVID-19 vaccine directed against the antigenic regions of the S protein, which are less prone to mutations.

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Section: Discussionmentioning

confidence: 99%

Production and Immunogenicity Assessment of LTp50: An Escherichia coli-Made Chimeric Antigen Targeting S1- and S2-Epitopes from the SARS-CoV-2/BA.5 Spike Protein

Wong-Arce,

Gonzalez-Ortega,

Romero-Maldonado

et al. 2024

Pharmaceuticals

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“…Recent research suggests that the adjuvanticity of LTB is mediated by enhancing dendritic cell turnover in the spleen and increasing their capacity to function as antigen-presenting cells when encountering T cells [ 36 ]. LTB also mediates the clustering of B and T cells, as well as the delay or arrest of T cell division after endocytosis or B-cell receptor (BCR) uptake of antigens in a ganglioside-dependent manner [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

A Recombinant Chimera Vaccine Composed of LTB and Mycoplasma hyopneumoniae Antigens P97R1, mhp390 and P46 Elicits Cellular Immunologic Response in Mice

et al. 2023

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Mycoplasma hyopneumoniae is the etiological agent of porcine enzootic pneumonia (EP), leading to a mild and chronic pneumonia in swine. Relative control has been attained through active vaccination programs, but porcine enzootic pneumonia remains a significant economic challenge in the swine industry. Cellular immunity plays a key role in the prevention and control of porcine enzootic pneumonia. Therefore, the development of a more efficient vaccine that confers a strong immunity against M. hyopneumoniae is necessary. In this study, a multi-antigen chimera (L9m6) was constructed by combining the heat-labile enterotoxin B subunit (LTB) with three antigens of M. hyopneumoniae (P97R1, mhp390, and P46), and its immunogenic and antigenic properties were assessed in a murine model. In addition, we compared the effect of individual administration and multiple-fusion of these antigens. The chimeric multi-fusion vaccine induced significant cellular immune responses and high production of IgG and IgM antibodies against M. hyopneumoniae. Collectively, our data suggested that rL9m6 chimera exhibits potential as a viable vaccine candidate for the prevention and control of porcine enzootic pneumonia.

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“…Effective immunotherapy relies on the choice of the antigen, and gangliosides, especially GM3, play an important role in it . However, GM3 is poorly immunogenic, which limits its application. − Neu5Gc GM3 is considered to have higher immunogenicity and two clinical trials targeting Neu5Gc GM3 are undergoing. , A phase Ib/IIa study of Neu5Gc GM3-VSSP for advanced melanoma patients showed encouraging observations: 9 of 22 patients survived more than 1 year, with 7 of them living more than 2 years. Recently, a variety of GM3-targeting cancer immunotherapies have been evaluated and also showed an evident effect. , The discovery of novel GM3 derivatives with higher immunogenicity has significant meaning for cancer immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

One-Pot Enzymatic Synthesis and Biological Evaluation of Ganglioside GM3 Derivatives as Potential Cancer Immunotherapeutics

et al. 2022

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Cancer is a leading cause of death worldwide. Recent research studies have revealed that GM3 derivatives have considerable promise as potential therapeutic agents for cancer. To discover novel GM3 derivatives as potential antitumor agents, a one-pot enzymatic synthesis was established, yielding 14 GM3 derivatives in high total yields (22–41%). Subsequently, the inhibitory activities of GM3 derivatives were assessed by wound-healing assays and Transwell assays and tumor-bearing animal models. Among all the GM3 derivatives, N-12 showed excellent migration and invasion inhibitory effects in cells and marked antitumor activity in C57BL/6 mice. The subsequent analysis of cancer tissues and serum samples revealed that N-12 induces tumor inhibition, which was closely related to immune response. Taken together, N-12 can be further developed as an effective therapeutic for the treatment of cancer. An RNA-sequencing (RNA-seq) analysis was then performed and indicated that the antitumor mechanism of N-12 involved focal adhesion and ECM-receptor interaction signaling pathways.

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Immunomodulatory regulation by heat-labile enterotoxins and potential therapeutic applications

Cited by 3 publications

References 99 publications

Production and Immunogenicity Assessment of LTp50: An Escherichia coli-Made Chimeric Antigen Targeting S1- and S2-Epitopes from the SARS-CoV-2/BA.5 Spike Protein

Production and Immunogenicity Assessment of LTp50: An Escherichia coli-Made Chimeric Antigen Targeting S1- and S2-Epitopes from the SARS-CoV-2/BA.5 Spike Protein

A Recombinant Chimera Vaccine Composed of LTB and Mycoplasma hyopneumoniae Antigens P97R1, mhp390 and P46 Elicits Cellular Immunologic Response in Mice

One-Pot Enzymatic Synthesis and Biological Evaluation of Ganglioside GM3 Derivatives as Potential Cancer Immunotherapeutics

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