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.

Takayuki Nakagawa,Kazufumi Katayama,Yukichi Ishioka,Ken J Ishii,Morio Nagira,Motoyasu Onishi,Takayuki Kanazawa,Soichi Tofukuji,Tetsuya Tanino,Akira Kugimiya,Takuya Yamamoto,Takeshi Itoh

doi:10.3389/fimmu.2021.803090

Abstract

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.

Highlights

Despite the large number of clinical trials of cancer peptide vaccines, no human cancer peptide vaccine has been approved to date [1]
Direct binding of the amphiphilic chain to CpG ODNs has been reported to enhance its accumulation in draining lymph nodes (LNs) by binding to albumin after injection, leading to antigenpresenting cell (APC) activation and increased T cell responses in draining LNs [3]
We designed an amphiphilic chain bound to the complementary strand of ODN2006 (B-type CpG ODN), and its efficacy and safety profiles have been confirmed in clinical trials [8]

Summary

Introduction

Despite the large number of clinical trials of cancer peptide vaccines, no human cancer peptide vaccine has been approved to date [1]. The efficacy and tolerability of CpG ODNs have been demonstrated in a large number of clinical trials [8]; CpG ODN modification is a promising approach for developing effective and safe cancer peptide vaccines. A CpG ODN combined with an amphiphilic tail has been reported to enhance the accumulation of draining LNs via albumin-hitchhiking and increase CD8+ T cell responses, which can maximize the anti-tumor effects of cancer peptide vaccines [3]. The immunological mechanisms have not been fully investigated to identify key players in the adjuvanticity of draining LN-targeting CpG ODNs. a previous structure–activity relationship study demonstrated that the agonistic activities of CpG ODNs for TLR9 were altered by modifying the 20-mer oligonucleotide sequence [11]. The direct modification can potentially alter the immunostimulatory effects of CpG ODNs and may cause an unpredictable immunotoxicity

Methods

Results

Conclusion