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Order Picornavirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
Miermont et al. (2008) employed the CPMV virions for the development of the carbohydrate-based antitumor vaccines. The Tn antigen GalNAc-α-O-Ser/Thr was chosen as the model antigen to be conjugated to CPMV capsid. The Tn antigen is a tumor associated carbohydrate antigen (TACA) overexpressed on the surface of a variety of cancer cell surfaces including breast, colon, and prostate cancer, rendering it an excellent immunotherapy target. The Tn was derivatized with either a maleimide or a bromoacetamide moiety that was conjugated selectively to the previously described cysteine mutant of CPMV. The antibodies generated in the immunized mice were able to recognize Tn antigens presented in their native conformations on the surfaces of breast cancer cells (Miermont et al. 2008).
Peptide Vaccine
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
Joel Lim Whye Ern, Tan Shen Leng, Tee Yi Na, Palaniarajan Vijayaraj Kumar
For example, a MAP system for glycoimmunogens that is used in vaccination is the Tn-antigenic dendrimer which was researched by Bay et al. where the tetrameric core structure is derivatized with the Tn-antigen and with a Th-cell stimulatory peptide (Niederhafner, Šebestík, and Ježek 2003; Bay et al. 1997). This derivatization showed a favorable result because it can react with the monoclonal antibodies against Tn. A G5-PAMAM dendrimer has been put into use which acts as a carrier of the Tn-antigen. The resulting glycoconjugates were evaluated as vaccine candidates in comparison with a carrier protein conjugated to a monomer, dimer, or trimer of the Tn-antigen. The result of the test shows that the Tn-antigen dendrimer conjugates induced zero-antibody reactions, and thus no immunogenicity, meanwhile Tn-antigen conjugated with a carrier protein showed an increase to antibody reactions (Boas and Heegaad 2004).
The Development of Improved Therapeutics through a Glycan- “Designer” Approach
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Abnormal O-glycosylation is often associated with various malignancies. For example, Tn antigen is adenocarcinoma-associated carbohydrate antigen built of D-GalNac unit α-linked to a Serine or Threonine amino acids (α-GalNAc-O-Ser/Thr glycan). One of the cancer vaccine constructs aimed to use the Tn glycan as a conjugate to Mucin-6 protein. Mucin-6 is a secretory O-glycosylated protein normally found at high levels in stomach but also aberrantly expressed on different carcinoma types and metastatic tumor cells. The immunology data showed that glycosylation of MU6 protein with the Tn glycan modulates immunogenicity by inducing IL-17 responses and by an efficient presentation of the antigen to CD4+T cells (Freire et al., 2006). The research conducted by Freire et.al (Freire et al., 2006) is an excellent example of strategic glycan designer approach, where different constructs were synthesized using in vitro enzymatic method (Fig. 20.1). To obtain MUC6 proteins researchers used E. coli expression system which allowed them to introduce various modifications in glycosylation sites of the protein. The protein was purified using NTA-agarose and C18 column separation methods followed by verification of the recombinant glycoprotein using high performance liquid chromatography (HPLC). To conjugate MUC6 with Tn antigen in vitro glycosylation was the method of choice using ppGAlNac transferase enzyme, with subsequent analysis of immunological properties in various in vitro and in vivo assays.
What are the diagnostic capabilities of glycans for breast cancer?
Published in Expert Review of Molecular Diagnostics, 2023
Since O-GalNAc is most commonly found in mucins, it is often referred to mucin-type O-glycans. Changes in mucin-type O-glycans have been observed in over 90% of breast cancers, suggesting that abnormal mucin-type O-glycans levels can also be used as a diagnostic marker of breast cancer [46]. Compared with O-glycans from normal mucins, malignant transformation is frequently accompanied highly sialylated and less sulfated glycopattern, in which O-glycans are commonly truncated, presenting as Tn and T antigens, and their sialylated versions [52]. Changes in mucin-type O-GalNAc glycosylation plays an important role in breast cancer growth and metastasis. The elevated Galectin-3 in breast cancer patients could interact with MUC1 carrying the core 1 glycan (T antigen) and enhance tumor cell aggregation [53]. Epithelial originated tumors including breast, colon, lung, and pancreas display high expression levels of Tn and sTn antigens [54]. Babino et al. found that Tn antigen could be used as a biomarker for the early diagnosis of breast cancer [55]. In addition, the aberrantly glycosylated MUC1 in serum has been approved as a biomarker for monitoring breast cancer progression and treatment [40,56,57].
Monoclonal antibody as a targeting mediator for nanoparticle targeted delivery system for lung cancer
Published in Drug Delivery, 2022
Nasrul Wathoni, Lisa Efriani Puluhulawa, I Made Joni, Muchtaridi Muchtaridi, Ahmed Fouad Abdelwahab Mohammed, Khaled M. Elamin, Tiana Milanda, Dolih Gozali
Wang, Liu, et al. (2015) conducted another study in which they used anti-EGFR to deliver gemcitabine nanoparticles to patients with NSCLC. In vitro test results performed on A549 cells showed an increase in cellular uptake, observed by measuring the fluorescence intensity of cells treated with anti-EGFR nanoparticles compared to cells treated without-anti-EGFR nanoparticles (Wang & Zhou, 2015). LFC131 is likewise a monoclonal antibody against the CXCR4 receptor, which is highly expressed in lung cancer. LFC131 can enhance the accumulation of doxorubicin nanoparticles made of PLGA polymer and can efficiently deliver drugs to A549 cells (Chittasupho et al., 2014). In another study, Tn antigen was also used in nanoparticle formulation with chitosan polymer to deliver doxorubicin. The results revealed that cellular absorption increased while cell viability decreased. Tn antigen is widely used as antibodies specific and a lung cancer-specific antigen (Castro et al., 2021).
Inhibition of O-glycosylation aggravates GalN/LPS-induced liver injury through activation of ER stress
Published in Immunopharmacology and Immunotoxicology, 2021
Dongkui Xu, Zhenguo Zhao, Yixian Li, Chao Shang, Lijie Liu, Jiaxu Yan, Ying Zheng, Zongmei Wen, Tao Gu
Glycosylation is the enzymatic addition of carbohydrate chains to proteins, which is the most common post-translational modification on many membrane-associated and secreted proteins [1,2]. Glycosylation can significantly affect a variety of fundamental biological processes [3]. According to sugar-amino acid linkages, glycosylation can be divided into two major types: N-glycosylation (Asn-linked) and O-glycosylation (Ser/Thr-linked) [4]. N-glycosylation is well-studied and predictable, whereas O-glycosylation is more complex and less elucidated [5]. O-glycosylation is essential for protein function, including protein structure, folding, stability, localization, and recognition, etc., and can also modulate enzyme activity and cell-to-cell and cell-to-extracellular matrix (ECM) interactions [6,7]. Many carcinomas exhibit aberrant O-glycosylation and produce truncated O-glycans, such as Tn/STn antigen [8,9]. Pathological exposure of Tn antigen on the cell surface or secreted proteins may promote cancer progression and metastasis [9–11]. In addition, aberrant O-glycosylation may play a role in systemic inflammation, ranging from leukocyte trafficking to initiation of innate immunity, which manifests as pro- or anti-inflammatory effects under certain conditions [12–14]. So far the specific functions of O-glycosylation during inflammation remain to be determined. Understanding the molecular mechanisms of O-glycosylation in the regulation of inflammation may lead to a greater appreciation of the related diseases involving altered O-glycosylation.