The development of effective
immunoadjuvants for
tumor immunotherapy is of fundamental importance. The use of Mycobacterium bovis bacillus Calmette-Guérin
cell wall skeleton (BCG-CWS) in
tumor immunotherapy has been examined in various clinical applications. Because BCG-CWS is a macromolecule that cannot be chemically synthesized, the development of an alternative synthetic molecule is necessary to ensure a constant supply of adjuvant. In the present study, a new adjuvant was designed based on the structure of macrophage-activating
lipopeptide (MALP)-2, which is a
Toll-like receptor (TLR)-2
ligand similar to BCG-CWS. Macrophage-activating lipopeptide-2, [S-(2,3-bispalmitoyloxypropyl)Cys (P2C) - GNNDESNISFKEK], originally identified in a Mycoplasma species, is a
lipopeptide that can be chemically synthesized. A
MALP-2 peptide was substituted with a functional motif, RGDS, creating a novel molecule named P2C-RGDS. RGDS was selected because its sequence constitutes an
integrin-binding motif and various
integrins are expressed in immune cells including dendritic cells (DCs). Thus, this motif adds functionality to the
ligand. P2C-RGDS activated DCs and splenocytes more efficiently than
MALP-2 over short incubation times in vitro, and the RGDS motif contributed to their activation. Furthermore, P2C-RGDS showed higher activity than
MALP-2 in inducing migration of DCs to draining lymph node, 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 constitutes a first step in the development of stronger synthetic adjuvants in the future.