A Synthetic MUC1 Anticancer Vaccine Containing Mannose Ligands for Targeting Macrophages and Dendritic Cells

Glaffig, Markus; Stergiou, Natascha; Hartmann, Sébastian; Schmitt, Edgar; Kunz, Horst

doi:10.1002/cmdc.201700646

Cited by 54 publications

(38 citation statements)

References 42 publications

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“…The C-terminal coupling of MUC1 glycopeptides to a vaccine carrier has been studied before. 21 As antibodies against the SAPDTRPAP region were thought to be important for tumor cell binding, MUC1 peptide sequence 29 was designed with SAPDTRPAP moved closer to the N-terminus (Scheme 2), which would be more accessible to B cell binding. A GalNAc moiety was introduced onto the threonine residue in the SAPDTRPAP region leading to glycopeptide 30 to explore the effect of glycosylation.…”

Section: Resultsmentioning

confidence: 99%

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Yin

McKay

et al. 2018

J. Am. Chem. Soc.

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Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUCl antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qβ carrier with MUC1 glycopeptides containing 20–22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qβ-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qβ-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.

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Section: Resultsmentioning

confidence: 99%

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Yin

McKay

et al. 2018

J. Am. Chem. Soc.

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“…[137,139,140] Frequently, a common strategy to trigger an efficient DCmediated immune response consists of combining sugar epitopes for CLRs and other ligands to co-stimulate Toll-like receptors, achieving for instance effective antitumor responses. [138,141] DC-SIGN internalization capabilities have been also exploited for intracellular delivery of therapeutic agents, [142] and for this purpose, sugar-coated liposomes are ideal platforms. In general, micelles and liposomes are quick pathways to afford enormous multivalent structures from suitable function-alized lipids.…”

Section: Relevant Interacting Monosaccharides and Glycansmentioning

confidence: 99%

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

et al. 2020

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Carbohydrates play a pivotal role in intercellular communication processes. In particular, glycan antigens are key for sustaining homeostasis, helping leukocytes to distinguish damaged tissues and invading pathogens from healthy tissues. From a structural perspective, this cross-talk is fairly complex, and multiple membrane proteins guide these recognition processes, including lectins and Toll-like receptors. Since the beginning of this century, lectins have become potential targets for therapeutics for controlling and/or avoiding the progression of pathologies derived from an incorrect immune outcome, including infectious processes, cancer, or autoimmune diseases. Therefore, a detailed knowledge of these receptors is mandatory for the development of specific treatments. In this review, we summarize the current knowledge about four key C-type lectins whose importance has been steadily growing in recent years, focusing in particular on how glycan recognition takes place at the molecular level, but also looking at recent progresses in the quest for therapeutics.

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“…Glaffig et al developed anticancer vaccines where two mannosyl glycolic acids were linked to both amino groups of the N-terminal lysine of a peptide derived from mucin 1 protein (which is overexpressed by several cancers) [ 66 ]. The mannosylated antigens were internalized via endocytosis by DCs and macrophages 2–4 orders of magnitude faster than non-mannosylated vaccine candidates.…”

Section: Carbohydrate-based Adjuvantsmentioning

confidence: 99%

Carbohydrate Immune Adjuvants in Subunit Vaccines

et al. 2020

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Modern subunit vaccines are composed of antigens and a delivery system and/or adjuvant (immune stimulator) that triggers the desired immune responses. Adjuvants mimic pathogen-associated molecular patterns (PAMPs) that are typically associated with infections. Carbohydrates displayed on the surface of pathogens are often recognized as PAMPs by receptors on antigen-presenting cells (APCs). Consequently, carbohydrates and their analogues have been used as adjuvants and delivery systems to promote antigen transport to APCs. Carbohydrates are biocompatible, usually nontoxic, biodegradable, and some are mucoadhesive. As such, carbohydrates and their derivatives have been intensively explored for the development of new adjuvants. This review assesses the immunological functions of carbohydrate ligands and their ability to enhance systemic and mucosal immune responses against co-administered antigens. The role of carbohydrate-based adjuvants/delivery systems in the development of subunit vaccines is discussed in detail.

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A Synthetic MUC1 Anticancer Vaccine Containing Mannose Ligands for Targeting Macrophages and Dendritic Cells

Cited by 54 publications

References 42 publications

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

Carbohydrate Immune Adjuvants in Subunit Vaccines

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