Endogenous lectins as targets for drug delivery

Yamazaki, Noboru; Kojima, Shuji; Bovin, Nicolai V.; André, Sabine; Gabius, Sigrun; Gabius, Hans‐Joachim

doi:10.1016/s0169-409x(00)00071-5

Cited by 186 publications

(107 citation statements)

References 78 publications

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“…Targeting the asialoglycoprotein receptor and the mannose receptor in the liver, for example, are early examples of this approach. [26,27] With the recent identification/enumeration of the C-type lectins of the immune system, [6] and the finding that some of these newly identified lectins appear capable of modulating cytokine production by DCs in certain settings, targeting lectins of the innate immune system, and DCs in particular, appears to offer a novel way of shaping the ensuing adaptive immune response. The aforementioned DEC-205 antibody-targeting work is a powerful example of how targeting DC-expressed lectins in vivo gives one fine control over the polarization (Th1, Th2 or Treg) and strength of the T cell response.…”

Section: Discussionmentioning

confidence: 99%

Carbohydrate‐Mediated Targeting of Antigen to Dendritic Cells Leads to Enhanced Presentation of Antigen to T Cells

et al. 2008

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The unique therapeutic value of dendritic cells (DCs) for the treatment of allergy, autoimmunity and transplant rejection is predicated upon our ability to selectively deliver antigens, drugs or nucleic acids to DCs in vivo. Here we describe a method for delivering whole protein antigens to DCs based on carbohydrate-mediated targeting of DC-expressed lectins. A series of synthetic carbohydrates was chemically-coupled to a model antigen, ovalbumin (OVA), and each conjugate was evaluated for its ability to increase the efficiency of antigen presentation by murine DCs to OVA-specific T cells (CD4 + and CD8 + ). In vitro data are presented that demonstrate that carbohydrate modification of OVA leads to a 50-fold enhancement of presentation of antigenic peptide to CD4 + T cells. A tenfold enhancement is observed for CD8 + T cells; this indicates that the targeted lectin(s) can mediate crosspresentation of antigens on MHC class I. Our data indicate that the observed enhancements in antigen presentation are unique to OVA that is conjugated to complex oligosaccharides, such as a highmannose nonasaccharide, but not to monosaccharides. Taken together, our data suggest that a DC targeting strategy that is based upon carbohydrate-lectin interactions is a promising approach for enhancing antigen presentation via class I and class II molecules.

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Section: Discussionmentioning

confidence: 99%

Carbohydrate‐Mediated Targeting of Antigen to Dendritic Cells Leads to Enhanced Presentation of Antigen to T Cells

et al. 2008

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“…The aims of the present work were therefore to detect binding capacity and then, if positive, to characterize the influence of various types of Lewis antigens on the level of migration of these colon cancer cells. For this purpose, it is essential to synthesize the oligosaccharides and to link them to an inert carrier to mimic the high affinity-generating multivalency of their presentation in natural glycoconjugates, a route previously exploited for preparation of effective inhibitors for selectins and the galectin class of endogenous lectins (André et al, 1999(André et al, , 2001Gabius et al, 1993;Ohyama et al, 2002;Sanders et al, 1999;Simanek et al, 1998;Welply et al, 1994;Yamazaki et al, 2000). To exclude the possibility of exceptional behavior of a single line, we used four distinct cancer cell lines (HCT-15, LoVo, Colo-201, and DLD-1).…”

Section: Hittelet Et Almentioning

confidence: 99%

Binding Sites for Lewis Antigens Are Expressed by Human Colon Cancer Cells and Negatively Affect Their Migration

Hittelet

Camby

Nagy

et al. 2003

Laboratory Investigation

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SUMMARY:In colon cancer, endothelial cell selectins can promote tumor cell attachment via interactions with sialylated Lewis antigens present at the surface of tumor cells, thereby facilitating tumor cell arrest and transmigration into the extravascular space. However, it is not known whether Lewis antigens interact with colon tumor cells and modify their migration. Our aim was to detect the presence of binding sites on human tumor cells for Lewis a/x antigens and their sialylated derivatives in vitro and in vivo and to analyze their influence on migration of colon cancer cells. The immunocytochemical and histochemical levels of expression of the four Lewis antigens were quantitatively determined in four human colon cancer cell lines and in in vivo nude mice xenografts. The levels of expression of specific binding sites for these sugar epitopes were determined by synthetic neoglycoconjugates. The influence of binding of these carbohydrate ligands on cancer cell migration was quantitatively evaluated by computer-assisted phase-contrast videomicroscopy performed on Matrigel culture supports either left uncoated or coated with neoglycoconjugate presenting synthetic Lewis a , sialyl Lewis a , Lewis x , or sialyl Lewis x antigens. The influence of the calcium concentration in the culture medium on the Lewis antigen-mediated effects was checked. Human colon cancer cells expressed significant amounts of specific binding sites detected by the synthetic probes in addition to the oligosaccharide epitopes. The expression levels differed considerably between the four cell lines and between in vitro and in vivo specimens. Cell migration analysis revealed that the four Lewis antigens markedly decreased the levels of migration of the HCT-15 and LoVo cancer cells. This effect depends on the calcium concentration in the culture medium. Binding sites for Lewis epitopes are present on colon cancer cells. The functional relevance of these sites is indicated by the negative influence on cell migration of a matrix containing the oligosaccharides as ligand parts. (Lab Invest 2003, 83:777-787).

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“…Carbohydrates exhibit properties of potential interest when developing drug-delivery mechanisms, such as specificity in their interaction with their receptors (4) and the varied nature of potentially targetable receptors available (5). Macromolecular glycoconjugates, in particular, have shown some promise (6).…”

mentioning

confidence: 99%

LEAPT: Lectin-directed enzyme-activated prodrug therapy

Robinson

Charlton

Garnier

et al. 2004

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

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. We describe a bipartite drug-delivery system that exploits (i) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (ii) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an ␣-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of ␣-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzymeactivated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.

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Endogenous lectins as targets for drug delivery

Cited by 186 publications

References 78 publications

Carbohydrate‐Mediated Targeting of Antigen to Dendritic Cells Leads to Enhanced Presentation of Antigen to T Cells

Carbohydrate‐Mediated Targeting of Antigen to Dendritic Cells Leads to Enhanced Presentation of Antigen to T Cells

Binding Sites for Lewis Antigens Are Expressed by Human Colon Cancer Cells and Negatively Affect Their Migration

LEAPT: Lectin-directed enzyme-activated prodrug therapy

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