title: A molecular assembly system that renders antigens of choice highly repetitive for induction of protective B cell responses.
abstract: Virus like particles (VLPs) are known to induce potent B cell responses in the absence of adjuvants. Moreover, epitope-specific antibody responses may be induced by VLPs that contain peptides inserted in their immunodominant regions. However, due to steric problems, the size of the peptides capable of being incorporated into VLPs while still permitting capsid assembly, is rather limited. While peptides genetically fused to either the N- or C-terminus of VLPs present fewer assembly problems, the immune responses obtained against such epitopes are often limited, most likely because the epitopes are not optimally exposed. In addition, such particles may be less stable in vivo. Here, we show that peptides and proteins engineered to contain a free cys can be chemically coupled to VLPs formed from the hepatitis B core antigen (HBcAg) containing a lys in the immuno-dominant region. By using this approach steric hindrance of capsid assembly is abrogated. Peptides or protein coupled to VLPs in an oriented fashion are shown to induce strong and protective B cell responses even against self-epitopes in the absence of adjuvants. This molecular assembly system may be used to induce strong B cell responses against most antigens.
authors.affiliation: Cytos Biotechnology AG, CH-8952 Schlieren-Zürich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jegerlehner
authors.forename: Alain
authors.initials: A
authors.lastname: Tissot
authors.forename: Franziska
authors.initials: F
authors.lastname: Lechner
authors.forename: Peter
authors.initials: P
authors.lastname: Sebbel
authors.forename: Iris
authors.initials: I
authors.lastname: Erdmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Kündig
authors.forename: Thomas
authors.initials: T
authors.lastname: Bächi
authors.forename: Tazio
authors.initials: T
authors.lastname: Storni
authors.forename: Gary
authors.initials: G
authors.lastname: Jennings
authors.forename: Paul
authors.initials: P
authors.lastname: Pumpens
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Renner
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan; D001402:B-Lymphocytes / Q000276:immunology*; D001514:Bee Venoms / Q000201:enzymology / Q000276:immunology; D003432:Cross-Linking Reagents; D015195:Drug Design; D005260:Female; D006512:Hepatitis B Core Antigens / Q000235:genetics / Q000276:immunology*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology*; D007114:Immunization; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology; D007181:Inclusion Bodies, Viral / Q000235:genetics / Q000276:immunology*; D046911:Macromolecular Substances; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009842:Oligopeptides; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010455:Peptides; D010741:Phospholipases A / Q000276:immunology*; D011487:Protein Conformation; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000235:genetics / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000953:Antigens, Protozoan; D001514:Bee Venoms; D003432:Cross-Linking Reagents; C106990:Gra2 protein, Toxoplasma gondii; D006512:Hepatitis B Core Antigens; D016056:Immunodominant Epitopes; C031540:M-protein, influenza virus; D046911:Macromolecular Substances; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; D014761:Viral Hepatitis Vaccines; D014763:Viral Matrix Proteins; C085706:FLAG peptide; D010741:Phospholipases A