Conjugation of Ligands at the 5‘-End of CpG DNA Affects Immunostimulatory Activity
Identifieur interne : 003364 ( Main/Curation ); 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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<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>
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