Conjugation of Ligands at the 5‘-End of CpG DNA Affects Immunostimulatory Activity
Identifieur interne : 003364 ( Main/Exploration ); précédent : 003363; suivant : 003365Conjugation of Ligands at the 5‘-End of CpG DNA Affects Immunostimulatory Activity
Auteurs : Ekambar R. Kandimalla [États-Unis] ; Lakshmi Bhagat [États-Unis] ; Dong Yu [États-Unis] ; Yanping Cong [États-Unis] ; Jimmy Tang [États-Unis] ; Sudhir Agrawal [États-Unis, Oman]Source :
- Bioconjugate Chemistry [ 1043-1802 ] ; 2002.
Abstract
Bacterial DNA and synthetic oligonucleotides containing unmethylated CpG dinucleotides (CpG DNA) activate the vertebrate immune system and promote Th1-like immune responses. Several CpG DNAs are currently being tested in clinical trials as either alone or in combination with vaccines, antibodies, and allergens separately or as conjugates for a number of disease indications including cancers, allergies, and asthma. In this paper, we show that conjugation of an oligonucleotide and a CpG DNA through their 5‘-ends (5‘-5‘-linked DNA) significantly reduces the immunostimulatory activity of the CpG DNA. In addition, we found that the reduction in immunostimulatory activity of 5‘-5‘-linked CpG DNA depends on the size of the oligonucleotide conjugated to CpG DNA. Conjugation of a smaller group or molecule, such as a phosphorothioate group, at the 5‘-end of CpG DNA has an insignificant effect on immunostimulatory activity. However, conjugation of a mononucleotide, tetra- or longer oligonucleotide or a fluorescein molecule to the 5‘-end of a CpG DNA (5‘-5‘-linked DNA) significantly suppresses the immunostimulatory activity of CpG DNA. Surprisingly, conjugation of an oligonucleotide or a ligand through the 3‘-end of CpG DNA (3‘-3‘-linked DNA) has an insignificant effect on immunostimulatory activity. Studies of cellular uptake and activation of transcription factor NF-κB in J774 cells using fluorescein-conjugated CpG DNAs suggest that the differences in the immune stimulation of 5‘- and 3‘-end-conjugated CpG DNAs is not as a result of differences in their cellular uptake properties. These results suggest that for optimal immunostimulatory activity, ligands should not be attached at the 5‘-end of the CpG DNA.
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DOI: 10.1021/bc0200374
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Tel: 617-679-5501, Fax: 617-679-5542</wicri:regionArea><wicri:noRegion>Fax: 617-679-5542</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Bioconjugate Chemistry</title><title level="j" type="abbrev">Bioconjugate Chem.</title><idno type="ISSN">1043-1802</idno><idno type="eISSN">1520-4812</idno><imprint><publisher>American Chemical Society</publisher><date type="e-published">2002</date><date type="published">2002</date><biblScope unit="vol">13</biblScope><biblScope unit="issue">5</biblScope><biblScope unit="page" from="966">966</biblScope><biblScope unit="page" to="974">974</biblScope></imprint><idno type="ISSN">1043-1802</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1043-1802</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Bacterial DNA and synthetic oligonucleotides containing unmethylated CpG dinucleotides (CpG DNA) activate the vertebrate immune system and promote Th1-like immune responses. Several CpG DNAs are currently being tested in clinical trials as either alone or in combination with vaccines, antibodies, and allergens separately or as conjugates for a number of disease indications including cancers, allergies, and asthma. In this paper, we show that conjugation of an oligonucleotide and a CpG DNA through their 5‘-ends (5‘-5‘-linked DNA) significantly reduces the immunostimulatory activity of the CpG DNA. In addition, we found that the reduction in immunostimulatory activity of 5‘-5‘-linked CpG DNA depends on the size of the oligonucleotide conjugated to CpG DNA. Conjugation of a smaller group or molecule, such as a phosphorothioate group, at the 5‘-end of CpG DNA has an insignificant effect on immunostimulatory activity. However, conjugation of a mononucleotide, tetra- or longer oligonucleotide or a fluorescein molecule to the 5‘-end of a CpG DNA (5‘-5‘-linked DNA) significantly suppresses the immunostimulatory activity of CpG DNA. Surprisingly, conjugation of an oligonucleotide or a ligand through the 3‘-end of CpG DNA (3‘-3‘-linked DNA) has an insignificant effect on immunostimulatory activity. Studies of cellular uptake and activation of transcription factor NF-κB in J774 cells using fluorescein-conjugated CpG DNAs suggest that the differences in the immune stimulation of 5‘- and 3‘-end-conjugated CpG DNAs is not as a result of differences in their cellular uptake properties. These results suggest that for optimal immunostimulatory activity, ligands should not be attached at the 5‘-end of the CpG DNA.</div></front></TEI><affiliations><list><country><li>Oman</li><li>États-Unis</li></country><region><li>Massachusetts</li></region></list><tree><country name="États-Unis"><region name="Massachusetts"><name sortKey="Kandimalla, Ekambar R" sort="Kandimalla, Ekambar R" uniqKey="Kandimalla E" first="Ekambar R." last="Kandimalla">Ekambar R. 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