Synthetic lipopeptide adjuvants and Toll-like receptor 2—structure–activity relationships

Spohn, Renate; Buwitt-Beckmann, Ute; Brock, Roland; Jung, Günther; Ulmer, Artur J.; Wiesmüller, Karl‐Heinz

doi:10.1016/j.vaccine.2003.11.074

Cited by 127 publications

(142 citation statements)

References 41 publications

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“…1) were examined in a well established mouse model for mammary cancer (35). The multicomponent vaccine candidate 1 contains a tumor-associated glycopeptide derived from MUC1 (1, 3), the well-documented murine MHC class II restricted T helper epitope KLFAVWKITYKDT derived from polio virus (36), and the lipopeptide Pam 3 CysSK 4 , which is a potent agonist of Toll-like receptor 2 (TLR2) (37). Previously, the MUC1-derived glycopeptide SAPDTαGalNAc)RPAP, was identified as the antigenic-dominant domain of the tandem repeat of MUC1 (8,9).…”

Section: Resultsmentioning

confidence: 99%

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Lakshminarayanan¹,

Thompson

Wolfert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

278

260

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The mucin MUC1 is typically aberrantly glycosylated by epithelial cancer cells manifested by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and are susceptible to recognition by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Efforts to elicit CTLs and IgG antibodies against cancer-expressed MUC1 have not been successful when nonglycosylated MUC1 sequences were used for vaccination, probably due to conformational dissimilarities. Immunizations with densely glycosylated MUC1 peptides have also been ineffective due to impaired susceptibility to antigen processing. Given the challenges to immuno-target tumor-associated MUC1, we have identified the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of MUC1 resulting in a therapeutic response in a mouse model of mammary cancer. The vaccine is composed of the immunoadjuvant Pam 3 CysSK 4 , a peptide T helper epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three components was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs which recognized only nonglycosylated peptide. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control. As a result, immunization with the glycosylated tripartite vaccine was superior in tumor prevention. Besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.cancer vaccine | multicomponent | chemical synthesis | Tn antigen

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Section: Resultsmentioning

confidence: 99%

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Lakshminarayanan¹,

Thompson

Wolfert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

278

260

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“…[85][86][87][88] In contradistinction to Gram-negative LPS which is recognized by TLR4, 21,32-37 the lipopeptides signal via TLR2. 77,85,87,89 Although diacyl lipopeptides have been reported to be agonists of heterodimers of TLR2/ TLR6, 86,90,91 and triacylated species were thought to signal via TLR2/TLR1, 77,87,89 the recognition of the lipopeptides by TLR2 has been recently shown to be relatively independent of TLR1 and TLR6, and are mediated predominantly via TLR2. 92,93 Structural basis for the interactions of PAM 2 CSK 4 with TLR2 and PAM 3 CSK 4 with TLR2/TLR1.…”

Section: Tlr4 Agonists-lipopolysaccharide Monophosphoryl Lipid a Andmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…The other APCs uptake mechanisms are based on Toll-like receptors (TLRs) (Spohn et al, 2004). Known human Toll-like receptors constitute a family of ten protein members recognizing a wide variety of microbial lipophilic molecules (Park et al, 2009).…”

Section: Tumor Associated Carbohydrate Antigensmentioning

confidence: 99%

“…stimulation of long lasting, high affinity antibodies, preferably of the IgG isotypes against the carbohydrate antigens. Several groups have developed systematic research projects aimed at the synthesis of various vaccine compositions (Livingston, 1995;Danishefsky, Allen, 2000;Kudryashov et al, 2001;Roy, 2004;Spohn et al, 2004;Freire et al, 2006;Liakatos, Kunz, 2007;Roy, 2008;Franco, 2008;Guo, Wang, 2009;Roy, Shiao, 2011). In spite of the limited success encountered with traditional vaccine formulations based on vaccine carriers harboring the above carbohydrate antigens (Koganty, Yalamati, Jiang, 2008), considerable efforts have been recently devoted to the chemical design of glycodendrimers.…”

Section: Glycodendrimer Vaccinesmentioning

confidence: 99%

Glycodendrimers: versatile tools for nanotechnology

Roy

Shiao

Rittenhouse-Olson

2013

Braz. J. Pharm. Sci.

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Combining nanotechnology with glycobiology has triggered an exponential growth of research activities in the design of novel functional bionanomaterials (glyconanotechnology). More specifically, recent synthetic advances towards the tailored and versatile design of glycosylated nanoparticles namely glyconanoparticles, considered as synthetic mimetics of natural glycoconjugates, paved the way toward diverse biomedical applications. The accessibility of a wide variety of these structured nanosystems, in terms of shapes, sizes, and organized around stable nanoparticles have readily contributed to their development and applications in nanomedicine. In this context, glycosylated gold-nanoparticles (GNPs), glycosylated quantum dots (QDs), fullerenes, single-wall natotubes (SWNTs), and self-assembled glycononanoparticles using amphiphilic glycopolymers or glycodendrimers have received considerable attention to afford powerful imaging, therapeutic, and biodiagnostic devices. This review will provide an overview of the most recent syntheses and applications of glycodendrimers in glycoscience that have permitted to deepen our understanding of multivalent carbohydrate-protein interactions. Together with synthetic breast cancer vaccines, inhibitors of bacterial adhesions to host tissues including sensitive detection devices, these novel bionanomaterials are finding extensive relevance.

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Synthetic lipopeptide adjuvants and Toll-like receptor 2—structure–activity relationships

Cited by 127 publications

References 41 publications

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Potential adjuvantic properties of innate immune stimuli

Glycodendrimers: versatile tools for nanotechnology

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