A fully synthetic self-adjuvanting cancer vaccine candidate was constructed through covalent conjugation of invariant natural killer T (iNKT) cell ligand α-galactosylceramide (αGalCer) with sialyl Tn (STn), a representative tumor-associated carbohydrate antigen (TACA). This two-component vaccine STn-αGalCer is devoid of antigenic peptide, featuring the well-defined structure with high simplicity. STn-αGalCer showed remarkable efficacy in inducing antibody class switching from IgM to STn-specific IgG. Subtypes of IgG antibody were primarily IgG1 and IgG3.
The tumor‐associated antigen mucin 1 (MUC1) has been pursued as an attractive target for cancer immunotherapy, but the poor immunogenicity of the endogenous antigen hinders the development of vaccines capable of inducing effective anti‐MUC1 immunodominant responses. Herein, we prepared synthetic anti‐MUC1 vaccines in which the hydrophilic MUC1 antigen was N‐terminally conjugated to one or two palmitoyl lipid chains (to form amphiphilic Pam‐MUC1 or Pam2‐MUC1). These amphiphilic lipid‐tailed MUC1 antigens were self‐assembled into liposomes containing the NKT cell agonist αGalCer as an adjuvant. The lipid‐conjugated antigens reshaped the physical and morphological properties of liposomal vaccines. Promising results showed that the anti‐MUC1 IgG antibody titers induced by the Pam2‐MUC1 vaccine were more than 30‐ and 190‐fold higher than those induced by the Pam‐MUC1 vaccine and the MUC1 vaccine without lipid tails, respectively. Similarly, vaccines with the TLR1/2 agonist Pam3CSK4 as an adjuvant also induced conjugated lipid‐dependent immunological responses. Moreover, vaccines with the αGalCer adjuvant induced significantly higher titers of IgG antibodies than vaccines with the Pam3CSK4 adjuvant. Therefore, the non‐covalent assembly of the amphiphilic lipo‐MUC1 antigen and the NKT cell agonist αGalCer as a glycolipid adjuvant represent a synthetically simple but immunologically effective approach for the development of anti‐MUC1 cancer vaccines.
Peptides
are generally needed as T-helper epitopes in nicotine
vaccines to induce effective antibody responses, but the highly polymorphic
property of major histocompatibility complex (MHC) molecules may limit
opportunities of B cell to receive CD4+ T-cell help. Invariant
natural killer T (iNKT) cells recognize lipid antigens presented by
the nonpolymorphic CD1d molecule that is conserved in mammals to a
great extent. iNKT cells also display some similar functions to conventional
CD4+ T-helper cells, especially they license dendritic
cells stimulate antibody isotype switching by B cells. Herein, α-galactosylceramide
(αGalCer), a classical iNKT cell agonist, serves as an adjuvant
in synthetic nicotine vaccine candidates absent of peptide or protein.
Our study reveals that αGalCer displays better adjuvant activity
than Pam3CSK4 (a commonly used lipopeptide TLR
agonist). Remarkably, the covalent linker between the nicotine hapten
and αGalCer is not critical. Self-assembly of the lipid-tailed
nicotine and αGalCer into the liposome represents a structurally
simple but immunologically effective way to develop nicotine vaccines.
This is the first time to introduce the iNKT cell agonist as an adjuvant
to an antidrug vaccine. This discovery may contribute to improving
the efficacy of clinical candidate nicotine vaccines in the future.
Adipic acid diselenoester was developed as an efficient cross-linker for covalent protein conjugation with a variety of small molecular haptens, including mono- and disaccharides, peptide, fluorescence dye, and nicotine. Compared to the counterparts of N-hydroxysuccinimide (NHS) and p-nitrophenyl (PNP) linkers, the diselenoester linker demonstrates improved balance between reactivity and stability and coupling of haptens to proteins under mild conditions with high incorporation efficiency.
Along with N-hydroxysuccinimidyl, p-nitrophenyl, and phenylseleno esters, tetra- and penta-fluorophenyl esters were comparatively evaluated in term of their reactivity and hydrolytic stability. Their homobifunctional cross-linkers were prepared to conjugate proteins with small molecules, including carbohydrates, fluorescent dyes, and poly(ethylene glycol) monomethyl ether. The conjugations proceeded under mild conditions, affording the corresponding protein conjugates with good efficiency.
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