Immune therapeutic applications of stimulating TLR9 with B-Class and C-Class CpG oligos

Arthur M. Krieg,

Coley Pharmaceutical Group, Wellesley, MA, USA.

Unmethylated CpG dinucleotides in bacterial or viral DNA can engage the Toll-like receptor (TLR)9, thereby stimulating innate and adaptive immunity. These immune effects can be mimicked by synthetic oligodeoxynucleotides containing CpG motifs (CpG ODN). In humans only B cells and plasmacytoid dendritic cells (pDC) express TLR9 and are activated directly by CpG ODN. Depending on the structure and sequence of the CpG ODN, at least three distinct classes of immune effects can be induced. Depending on their class, CpG ODN activate B cells to proliferate and secrete immunoglobulin; and pDC to secrete a variety of Th1-like cytokines, chemokines, and type I interferons, and to express increased costimulatory molecules. When activated by CpG, pDC gain the ability to stimulate Th1-like T cell responses. CpG ODN induce immune defense mechanisms that protect against challenge with a wide range of infectious pathogens, and have shown therapeutic activity in animal models of allergic disease and cancer. CpG ODN are also extremely effective vaccine adjuvants, inducing Th1 responses in mice and primates with both specific antibody and CTL. A B-Class CpG ODN, 7909, is well tolerated and has shown activity as a monotherapy in phase I clinical trials in basal cell carcinoma, cutaneous T cell lymphoma, melanoma, non-Hodgkin’s lymphoma, and renal cell carcinoma. CpG 7909 is now in phase II clinical trials in combination with chemotherapy for lung cancer and melanoma. CpG 7909 also has shown outstanding activity as a humoral and cellular vaccine adjuvant for infectious disease and cancer vaccines. A C-Class oligo, 10101, has recently entered human clinical trials as a monotherapy for chronic hepatitis C virus infection.