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Immunostimulatory DNA sequences (ISS) containing CpG motifs induce interferon-alpha (IFN-alpha) and interferon-gamma (IFN-gamma) from human peripheral blood mononuclear cells and stimulate human B cells to proliferate and produce IL-6. We studied the motif and structural requirements for both types of activity using novel chimeric immunomodulatory compounds (CICs), which contain multiple heptameric ISS connected by non-nucleoside spacers in both linear and branched configurations. We found that the optimal motifs and structure for IFN-alpha production versus B cell activation differed. IFN-alpha production was optimal for CICs containing the sequences 5'-TCGXCGX and 5'-TCGXTCG, where X is any nucleotide. The presentation of multiple copies of these heptameric ISS with free 5'-ends via long, hydrophilic spacers, such as hexaethylene glycol, significantly enhanced the induction of IFN-alpha. Conversely, human B cell activity was predominantly dependent on ISS motif, with 5'-TCGTXXX and 5'-AACGTTC being the most active sequences. Thus, we found CICs could be 'programmed' for IFN-alpha production or B cell activation as independent variables. Additionally, CICs with separate human- and mouse-specific motifs were synthesized and these were used to confirm in vivo activity in mice. CICs may offer unique advantages over conventional ISS because identification of the optimal motifs, spacers and structures for different biological properties allows for the assembly of CICs exhibiting a defined set of activities tailored for specific clinical applications.

Novel chimeric immunomodulatory compounds containing short CpG oligodeoxyribonucleotides have differential activities in human cells