Chemical synthesis and immunological evaluation of new generation multivalent anticancer vaccines based on a Tn antigen analogue

Pifferi, Carlo; Ruiz‐de‐Angulo, Ane; Goyard, David; Tiertant, Claire; Sacristán, Nagore; Barriales, Diego; Berthet, Nathalie; Anguíta, Juan; Renaudet, Olivier; Fernández‐Tejada, Alberto

doi:10.1039/d0sc00544d

Cited by 19 publications

(17 citation statements)

References 89 publications

(87 reference statements)

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“…As well as improving strategies for TACA coupling to peptide epitopes that are able to be recognized by T cells, as well as novel polyvalent vaccine development and the characterization of strong and safe immune adjuvants, a promising approach could be vaccine developments based on chemically modified TACAs [337]. Some examples include an oxime-linked Tn analogue [338], a fluoro-substituted Sialyl-Tn [339], and a MUC1-β-TF [340].…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Berois

Pittini

Osinaga

2022

Cancers

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Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.

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Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Berois

Pittini

Osinaga

2022

Cancers

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“…Binding to a Tn-specific antibody showed a distinct preference for specific arrangements on the MAP system. The same group has prepared similar systems bearing the sialyl-Tn TACA ( 208 ) as well as Tn conjugated in a natural linkage to serine and one replaced with an oxime unit, where they showed that the oxime-linked Tn had superior immunotherapeutic properties in vivo ( 209 ).…”

Section: Glyco-nanotechnology and Cancer Immunotherapymentioning

confidence: 99%

Glycoconjugate Nanoparticle-Based Systems in Cancer Immunotherapy: Novel Designs and Recent Updates

Barchi

2022

Front. Immunol.

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For many years, cell-surface glycans (in particular, Tumor-Associated Carbohydrate Antigens, TACAs) have been the target of both passive and active anticancer immunotherapeutic design. Recent advances in immunotherapy as a treatment for a variety of malignancies has revolutionized anti-tumor treatment regimens. Checkpoint inhibitors, Chimeric Antigen Receptor T-cells, Oncolytic virus therapy, monoclonal antibodies and vaccines have been developed and many approvals have led to remarkable outcomes in a subset of patients. However, many of these therapies are very selective for specific patient populations and hence the search for improved therapeutics and refinement of techniques for delivery are ongoing and fervent research areas. Most of these agents are directed at protein/peptide epitopes, but glycans–based targets are gaining in popularity, and a handful of approved immunotherapies owe their activity to oligosaccharide targets. In addition, nanotechnology and nanoparticle-derived systems can help improve the delivery of these agents to specific organs and cell types based on tumor-selective approaches. This review will first outline some of the historical beginnings of this research area and subsequently concentrate on the last 5 years of work. Based on the progress in therapeutic design, predictions can be made as to what the future holds for increasing the percentage of positive patient outcomes for optimized systems.

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“…The low immunogenicity of tumor-associated carbohydrate antigens (TACAs), including the Tn antigen, is one of the major obstacles in the development of TACA-based antitumor vaccines. The immunogenicity can be enhanced by conjugation of TACA to a natural or synthetic immunostimulant carrier − or by synthetic modification of TACA if the modified antigen is recognized as foreign by the immune system, and the elicited immune response is cross-reactive to the native antigen expressed in the tumor tissue. − The fluorination of TACAs is an attractive approach because fluorinated carbohydrate epitopes are structurally similar to natural epitopes, , thus increasing the likelihood of generating cross-reactive antibodies. − In addition, deoxyfluorination (the replacement of an OH group with fluorine) increases the resistance of the glycosidic bond to hydrolysis, which can help overcome the sensitivity of carbohydrate-based vaccines to metabolic degradation . The synthesis of deoxyfluorinated TACA is challenging.…”

Section: Introductionmentioning

confidence: 99%

Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated T_N Antigen Analogues

et al. 2021

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The Tn antigen (GalNAcα1-Thr/Ser) is abundantly expressed in many tumors but rarely found in healthy tissues, which makes it an attractive epitope for antitumor immunotherapy. The use of the Tn antigen in the development of therapeutic antitumor vaccines is hampered by its low immunogenicity, which may be enhanced by deoxyfluorination of the GalNAc moiety. Here, we report the synthesis of protected 3-and 4-fluoro analogues of the threonine-containing Tn antigen. As the stereoselective synthesis of α-linked fluorinated GalNAc is difficult, we prepared a panel of C3 and C4 deoxyfluorinated galactosazide thiodonors and evaluated their stereoselectivity in the glycosylation of carbohydrate acceptors and threonine derivatives. Glycosylation of threonine derivatives with O-benzylated C4 fluoro donors gave only modest but usable αselectivity of α/β = 2.5−3/1. The use of acyl and silyl protection at the 3-and 6-positions of the C4 fluoro donors did not enhance the selectivity. Installing a 4,6-di-tert-butylsilylene-protecting group in C3 fluoro donors resulted in exclusive α-selectivity and reaffirmed the strong α-directing effect of this protective group in glycosylation with galacto-configured glycosyl donors. Article pubs.acs.org/joc

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Chemical synthesis and immunological evaluation of new generation multivalent anticancer vaccines based on a Tn antigen analogue

Abstract: A fully-synthetic anticancer vaccine candidate incorporating an hexadecavalent Tn antigen analogue display via oxime linkages induced tumor-specific IgG antibodies and cellular immune responses in mice coadministered with QS-21 as an adjuvant.

Cited by 19 publications

References 89 publications

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Glycoconjugate Nanoparticle-Based Systems in Cancer Immunotherapy: Novel Designs and Recent Updates

Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated T_N Antigen Analogues

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Chemical synthesis and immunological evaluation of new generation multivalent anticancer vaccines based on a Tn antigen analogue

Abstract: A fully-synthetic anticancer vaccine candidate incorporating an hexadecavalent Tn antigen analogue display via oxime linkages induced tumor-specific IgG antibodies and cellular immune responses in mice coadministered with QS-21 as an adjuvant.

Cited by 19 publications

References 89 publications

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Glycoconjugate Nanoparticle-Based Systems in Cancer Immunotherapy: Novel Designs and Recent Updates

Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated TN Antigen Analogues

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Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated T_N Antigen Analogues