S-540956, a CpG Oligonucleotide Annealed to a Complementary Strand With an Amphiphilic Chain Unit, Acts as a Potent Cancer Vaccine Adjuvant by Targeting Draining Lymph Nodes

Robust induction of cancer-antigen-specific CD8⁺ T cells is essential for the success of Cancer peptide vaccines, which are composed of a peptide derived from a cancer-specific antigen and an immune-potentiating Adjuvant, such as a Toll-like Receptor (TLR) agonist. Efficient delivery of a vaccine antigen and an Adjuvant to antigen-presenting cells in the draining lymph nodes (LNs) holds key to maximize vaccine efficacy. Here, we developed S-540956, a novel TLR9-agonistic Adjuvant consisting of B-type CpG ODN2006 (also known as CpG7909), annealed to its complementary sequence oligodeoxynucleotide (ODN) conjugated to a lipid; it could target both a Cancer peptide antigen and a CpG-adjuvant in the draining LNs. S-540956 accumulation in the draining LNs and activation of plasmacytoid dendritic cells (pDCs) were significantly higher than that of ODN2006. Mechanistic analysis revealed that S-540956 enhanced the induction of MHC class I peptide-specific CD8⁺ T cell responses via TLR9 in a CD4⁺ T cell-independent manner. In mice, the therapeutic effect of S-540956-adjuvanted with a human papillomavirus (HPV)-E7 peptide vaccine against HPV-E7-expressing TC-1 tumors was significantly better than that of an ODN2006-adjuvanted vaccine. Our findings demonstrate a novel Adjuvant discovery with the complementary strand conjugated to a lipid, which enabled draining LN targeting and increased ODN2006 accumulation in draining LNs, thereby enhancing the Adjuvant effect. Our findings imply that S-540956 is a promising Adjuvant for Cancer peptide vaccines and has a high potential for applications in various vaccines, including recombinant protein vaccines.

CpG oligonucleotide; adjuvant; cancer peptide vaccine; delivery system; draining lymph node.