title: DNA vaccine expressing the mimotope of GD2 ganglioside induces protective GD2 cross-reactive antibody responses.
abstract: The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly immunoglobulin (Ig)-M antibody responses in the immunized host. Here, we investigated whether interconversion of GD2 into a peptide mimetic form would induce GD2 cross-reactive IgG antibody responses in mice. Screening of the X(15) phage display peptide library with the anti-GD2 monoclonal antibody (mAb) 14G2a led to isolation of mimetic peptide 47, which inhibited the binding of 14G2a antibody to GD2-positive tumor cells. The peptide was also recognized by GD2-specific serum antibodies from a patient with neuroblastoma, suggesting that it bears an internal image of GD2 ganglioside expressed on the tumor cells. The molecular basis for antigenicity of the GD2 mimetic peptide, established by molecular modeling and mutagenesis studies, led to the generation of a 47-LDA mutant with an increased mimicry to GD2. Immunization of mice with peptide 47-LDA-encoded plasmid DNA elicited GD2 cross-reactive IgG antibody responses, which were increased on subsequent boost with GD2 ganglioside. The vaccine-induced antibodies recognized GD2-positive tumor cells, mediated complement-dependent cytotoxicity, and exhibited protection against s.c. human GD2-positive melanoma growth in the severe combined immunodeficient mouse xenograft model. The results from our studies provide insights into approaches for boosting GD2 cross-reactive IgG antibody responses by minigene vaccination with a protective epitope of GD2 ganglioside.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bolesta
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kowalczyk
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wierzbicki
authors.forename: Piotr
authors.initials: P
authors.lastname: Rotkiewicz
authors.forename: Barbara
authors.initials: B
authors.lastname: Bambach
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Tsao
authors.forename: Irena
authors.initials: I
authors.lastname: Horwacik
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kolinski
authors.forename: Hanna
authors.initials: H
authors.lastname: Rokita
authors.forename: Martin
authors.initials: M
authors.lastname: Brecher
authors.forename: Xinhui
authors.initials: X
authors.lastname: Wang
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Danuta
authors.initials: D
authors.lastname: Kozbor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D001666:Binding Sites, Antibody; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D003429:Cross Reactions; D005260:Female; D005732:Gangliosides / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000276:immunology; D016233:Immunotherapy, Active / Q000379:methods*; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy; D019151:Peptide Library; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D005732:Gangliosides; D007074:Immunoglobulin G; D019151:Peptide Library; D010455:Peptides; D019444:Vaccines, DNA; C019403:ganglioside, GD2