title: Highly specific auto-antibodies against claudin-18 isoform 2 induced by a chimeric HBcAg virus-like particle vaccine kill tumor cells and inhibit the growth of lung metastases.
abstract: Strategies for antibody-mediated cancer immunotherapy, such as active immunization with virus-like particle (VLP)-based vaccines, are gaining increasing attention. We developed chimeric hepatitis B virus core antigen (HBcAg)-VLPs that display a surface epitope of the highly selective tumor-associated cell lineage marker claudin-18 isoform 2 (CLDN18.2) flanked by a mobility-increasing linker. Auto-antibodies elicited by immunization with these chimeric HBcAg-VLPs in 2 relevant species (mouse and rabbit) bind with high precision to native CLDN18.2 at physiologic densities on the surface of living cells but not to the corresponding epitope of the CLDN18.1 splice variant that differs by merely one amino acid. The induced auto-antibodies are capable of efficiently killing CLDN18.2 expressing cells in vitro by complement-dependent and antibody-dependent cell-mediated cytotoxicity. Moreover, they provide partial protective immunity against the challenge of mice with syngeneic tumor cells stably expressing CLDN18.2. Our study provides a first proof-of-concept that immunization combining VLPs as antigen carriers with specific conformational epitopes of a highly selective differentiation antigen may elicit auto-antibodies with high cytocidal and tumoricidal potential.
authors.affiliation: Department of Internal Medicine III, Translational and Experimental Oncology, and Institute of Zoology, Johannes Gutenberg-University, Innsbruck, Austria.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Klamp
authors.forename: Jens
authors.initials: J
authors.lastname: Schumacher
authors.forename: Georg
authors.initials: G
authors.lastname: Huber
authors.forename: Christoph
authors.initials: C
authors.lastname: Kühne
authors.forename: Ulrich
authors.initials: U
authors.lastname: Meissner
authors.forename: Abderraouf
authors.initials: A
authors.lastname: Selmi
authors.forename: Thomas
authors.initials: T
authors.lastname: Hiller
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreiter
authors.forename: Jürgen
authors.initials: J
authors.lastname: Markl
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D016466:CHO Cells; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D057167:Claudins; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006512:Hepatitis B Core Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D020033:Protein Isoforms; D011817:Rabbits; D013274:Stomach Neoplasms / Q000276:immunology / Q000628:therapy; D058425:Vaccines, Virus-Like Particle / Q000276:immunology* / Q000494:pharmacology
chemical_list: D001323:Autoantibodies; C486683:CLDN18 protein, human; D019496:Cancer Vaccines; D057167:Claudins; D006512:Hepatitis B Core Antigens; D008565:Membrane Proteins; D020033:Protein Isoforms; D058425:Vaccines, Virus-Like Particle