Lipopeptide Derivatives of Bacterial Lipoprotein Constitute Potent Immune Adjuvants Combined with or Covalently Coupled to Antigen or Hapten

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Abstract
Lipopeptide analogues of the N-terminus of bacterial lipoprotein consisting of N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-(R)-cysteine (Pam3Cys) attached to one to five further amino acids [Pam3 Cys-Ser-Ser-Asn-Ala, Pam3 Cys-Ser-(Lys)4, Pam3 Cys-Ala-Gly, and Pam3 Cys-Ser] were investigated for biological activity. In vitro, the compounds proved to be potent activators for Balb/c splenocytes as determined by proliferation as says. When given in vivo in combination with SRBC, Pam3 cys-Ser and Pam3 Cys-Ala-Gly acted as immunoadjuvants enhancing the antigen specific IgM response after 7, and the IgG response after 14 days. In combination with dinitrophenylated bovine serun albumine (BSA(Dnp)), especially the amphiphilic and water-soluble lipohexapeptide Pam3 Cys-Ser-(Lys)4 constituted a potent immune adjuvant. The lipopeptide was able to fully replace Freund''s complete adjuvant (FCS) enhancing both anti-Dnp IgM and IgG in Bulb/c mice. The hapten Dnp was also coupled directly - or via the spacer molecule 1,6 diaminohexane (HMD) - to the synthetic lipopeptides. The chemically defined low-molecular-mass conjugates obtained were capable of inducing anti-hapten-specific IgM and IgG without further adjuvants or carriers. The anti-hapten responses induced by these chemically uniform lipopeptide-hapten conjugates were, however, less pronounced than the response to the conventional heterogeneous hapten-protein conjugates BSA(Dnp), and only a weak boost effect was observed. Our results show that defined lipopeptides are novel immunoadjuvant either combined with or covalently linked to antigens or haptens.