open access

https://hdl.handle.net/2115/46909

Adjuvant engineering for cancer immunotherapy : Development of a synthetic TLR2 ligand with increased cell adhesion

英語

2010-07

Wiley-Blackwell

Cancer Science

101(7)

1596-1603

It is essential to develop effective immunoadjuvants for tumor immunotherapy. Various applications of mycobacterium bovis bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) to tumor immunotherapy have been examined. Because the BCG-CWS is a macromolecule that cannot be synthesized, development of an alternative synthetic adjuvant is required for a stable supply. Here, we designed a new adjuvant based on the structure of macrophage-activating lipopeptide-2 (MALP-2), which is a TLR2 ligand same as BCG-CWS. MALP-2 (S-(2,3-bispalmitoyloxypropyl)Cys-Gly-Asn-Asn-Asp-Glu-Ser-Asn-Ile-Ser-Phe-Lys-Glu-Lys, P2C-GNNDESNISFKEK) is a lipopeptide identified from a Mycoplasma species that can be chemically synthesized. We substituted a functional motif peptide, RGDS, for bacterial origin in the structure of MALP-2, creating P2C-RDGS, a novel molecule. We selected RGDS because the RGDS sequence is an integrin-binding motif, and various integrins are expressed on immune cells, including dendritic cells (DCs). Thus, this motif adds functionality to the ligand. P2C-RGDS activated DCs in vitro as much as MALP-2, and the RGDS motif partially contributed to the DC activation. P2C-RGDS largely depended on the RGDS motif to induce IFN-γ from splenocytes. This suggests that the upregulation of lipopeptide adhesion correlates with the activation of immune cells. P2C-RGDS showed higher activity than MALP-2 in inducing IFN-γ production from splenocytes in vitro and cytotoxicity, and in inhibiting tumor growth in vivo. This process of designing and developing synthetic adjuvants has been named "adjuvant engineering", and the evaluation and improvement of P2C-RGDS is the first step in developing a stronger synthetic adjuvant in the future.

学術雑誌論文

Accepted Manuscript

The definitive version is available at www.blackwell-synergy.com

1347-9032

1349-7006