Adjuvant Compounds for Conjugated Synthetic Vaccines
Synthetic vaccines consist of well-defined chemically produced molecules and require two components: an antigen and an immune-stimulating adjuvant. In peptide-based synthetic vaccines the antigen is a peptide that contains a sequence (the epitope) that is specifically recognized by the T cell immune system while the adjuvant is often a ligand of one of Toll-like receptors (TLR’s) that provides a “danger signal” and expands specific T cells. In this invention an improved adjuvant is described that can be used as the entity covalently attached to any synthetic peptide sequence.
This technology builds on a well-known design of conjugated vaccines comprising synthetic lipopeptides, in which the lipophilic TLR-2 agonist is attached to the N-terminus of synthetic antigenic peptide. Researchers from Leiden University have previously shown that classical TLR2 ligand-conjugated peptide vaccines has strong T cell activation potency in vivo and can control aggressive tumor growth. The compound contains a defined lipidcomponent which can be covalently attached to any synthetic peptide sequence. The adjuvant compound retains its strong adjuvanticity upon conjugation but possesses much improved physicochemical properties as compared to established lipid-based synthetic vaccines. The synthesis of the conjugatable TLR-2 agonist is accomplished by the methods of solution phase organic chemistry and subsequently it is readily coupled to a peptide sequence preassembled on solid-phase by standard method of peptide chemistry. The finished conjugate is liberated from the solid-phase and purified by the techniques common in the preparation of peptide-based vaccines.
The conjugable TLR2 lipopeptide adjuvant platform is suited to augment the immunogenicity of synthetic peptidebased vaccines to any pathogen or malignancy of which sequence information of immunogenic epitopes is
available. Especially for personalized vaccines for cancer patients this adjuvant offers a flexible system to swiftly conjugate multiple peptide sequences of tumor-specific mutated neo-epitopes.
- The novel synthetic adjuvant attached to the peptide retains its immunogenic potential.
- No detrimental effect on the solubility and stability of the peptide vaccine.
- Low toxicity, low side effects, no risk of biogenic contaminants and appropriate physicochemical properties.
- Preparation by standard synthetic methods of the field.
- Joint delivery of both components of the vaccine what is beneficial for optimal immune response induction with the low risk of adverse side effects.
- Peptide based vaccines
- Personalized vaccines
A solution synthesis of a conjugatable derivative of the TLR-2 agonist on gram-scale is developed as well as a general approach to the solid-phase synthesis of the lipopeptides connected to this adjuvant.
Immunological characterization of the TLR-2 agonist has shown:
- Strong TLR2 activation of reporter cell lines;
- Functional maturation of human dendritic cell cultures; and
- Improvement of antigen presentation of conjugated synthetic peptide harboring neo-epitope sequence to melanoma patient-derived human T cells.
Patent application submitted