Glyco-epitope Diversity: an Evolving Area of Glycomics Research and Biomarker Discovery

Wang, Guoyin

doi:10.4172/jpb.10000e24

Cited by 5 publications

(3 citation statements)

References 62 publications

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“… 30,31 Whether this is the same in humans needs further investigation. While glycans can affect the immunogenicity of proteins by presenting as a glycoepitope, 32 glycans can also shield other epitopes from T cells 33 and antibodies, 34 regulate presentation of neighboring epitopes, 35 or be a part of a specific peptide epitope (glycopeptide epitope). 36 Due to the significant impact of N2118Q mutation on FVIII immunogenicity in our gene therapy–treated HA mice, we considered the possibility of a potential glyco or glycopeptide epitope around the N2118 site.…”

Section: Discussionmentioning

confidence: 99%

Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII

Kooi¹,

Wang

Fan³

et al. 2022

Blood Advances

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The most significant complication in hemophilia A treatment is the formation of inhibitors against factor VIII (FVIII) protein. Glycans and glycan-binding proteins are central to a properly functioning immune system. This study focuses on whether glycosylation of FVIII plays an important role in induction and regulation of anti-FVIII immune responses. We investigated the potential roles of four N-glycosylation sites including N41 and N239 in the A1 domain, N1810 in the A3 domain, and N2118 in the C1 domain of FVIII in moderating its immunogenicity. Glycomics analysis of plasma derived FVIII revealed that sites N41, N239, and N1810 contain mostly sialylated complex glycoforms, while high mannose glycans dominate at site N2118. A missense variant that substitutes Asparagine (N) to Glutamine (Q) was introduced to eliminate glycosylation on each of these sites. Following gene transfer of plasmids encoding BDD-FVIII and each of these four FVIII variants, it was found that specific activity of FVIII in plasma remained similar among all treatment groups. Slightly increased or comparable immune responses in N41Q, N239Q, and N1810Q FVIII variant plasmids treated mice and significantly decreased immune responses in N2118Q FVIII plasmid treated mice were observed when compared to BDD-FVIII plasmid treated mice. The reduction of inhibitor response by N2118Q FVIII variant was also demonstrated in AAV-mediated gene transfer experiments. Furthermore, a specific glycopeptide epitope surrounding the N2118 glycosylation site was identified and characterized to activate T cells in a FVIII-specific proliferation assay. These results indicate that N-glycosylation of FVIII can have significant impact on its immunogenicity.

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Section: Discussionmentioning

confidence: 99%

Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII

Kooi¹,

Wang

Fan³

et al. 2022

Blood Advances

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“…By definition, a glycoepitope refers to a carbohydrate moiety that is recognized by a mAb or other glycan-binding protein [60]. While mAbs that only bind monosaccharide units (glycan-binding mAbs) exist, their affinity is usually much lower than protein-specific mAbs with equilibrium dissociation constant (K D ) values in the micromolar (µM) range compared to nanomolar (nM) range, respectively [61,62].…”

Section: Mucin Epitopes Arising From An Altered Glycomementioning

confidence: 99%

Antibody-Drug Conjugates Targeting Tumor-Specific Mucin Glycoepitopes

Brassard¹,

Hughes²,

Roskelley³

et al. 2022

Front. Biosci. (Landmark Ed)

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Finding the ideal epitope to target is a key element for the development of an antibody-drug conjugate (ADC). To maximize drug delivery to tumor cells and reduce side effects, this epitope should be specific to cancer cells and spare all normal tissue. During cancer progression, glycosylation pathways are frequently altered leading to the generation of new glycosylation patterns selective to cancer cells. Mucins are highly glycosylated proteins frequently expressed on tumors and, thus, ideal presenters of altered glycoepitopes. In this review, we describe three different types of glycoepitopes that are recognized by monoclonal antibodies (mAb) and, therefore, serve as ideal scaffolds for ADC; glycan-only, glycopeptide and shielded-peptide glycoepitopes. We review pre-clinical and clinical results obtained with ADCs targeting glycoepitopes expressed on MUC1 or podocalyxin (Podxl) and two mAbs targeting glycoepitopes expressed on MUC16 or MUC5AC as potential candidates for ADC development. Finally, we discuss current limits in using glycoepitope-targeting ADCs to treat cancer and propose methods to improve their efficacy and specificity.

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“…Por otra parte, la exposición de los antígenos oncofetales puede desenmascarar epítopes que provocan respuesta inmune. Varios estudios muestran que la vacunación de pacientes con carcinomas de seno usando carbohidratos con el determinante Tn lleva a un mejor pronóstico [86]. Estas estructuras asociadas a tumores interactúan con lectinas de tipo C sobre células presentadoras de antígenos, dendritas y macrófagos, los cuales son importantes para tratamientos de inmunoterapia activa del cáncer.…”

Section: Patologías Asociadas a Glicoproteínasunclassified

Introducción al análisis estructural de proteínas y glicoproteínas

Castro¹,

Reyes-Montaño²

2020

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Los seres vivos están conformados por gran diversidad de proteínas con diferentes características físicas, químicas, estructurales y funcionales. Para entender la función de una proteína se necesita conocer su secuencia y, mejor aún, su estructura tridimensional. Hoy en día es significativo el incremento en el número de secuencias reportadas, al igual que el aumento en la determinación del número de estructuras tridimensionales por métodos experimentales e in silico. Todo este conjunto de estudios ha sido de gran importancia en la formulación de los conceptos modernos de la bioquímica y ha permitido entender la relación que se da entre estructura y función de las proteínas, esto es una premisa fundamental que guía el quehacer bioquímico. En el presente texto brindamos una descripción general de algunos de los aspectos más relevantes sobre los componentes estructurales de proteínas y glicoproteínas, así como algunas técnicas que se han usado para estudiar cada uno de los niveles estructurales que se encuentran en ellas.

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Glyco-epitope Diversity: an Evolving Area of Glycomics Research and Biomarker Discovery

Cited by 5 publications

References 62 publications

Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII

Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIII

Antibody-Drug Conjugates Targeting Tumor-Specific Mucin Glycoepitopes

Introducción al análisis estructural de proteínas y glicoproteínas

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