%0 Journal Article %J Cancer Research %D 2005 %T DNA vaccine expressing the mimotope of GD2 ganglioside induces protective GD2 cross-reactive antibody responses %A Elizabeth Bolesta %A Aleksandra Kowalczyk %A Andrzej Wierzbicki %A Piotr Rotkiewicz %A Barbara Bambach %A Chun-Yen Tsao %A Irena Horwacik %A Andrzej Koliński %A Hanna Rokita %A Martin Brecher %A Xinhui Wang %A Soldano Ferrone %A Danuta Kozbor %K Active %K Active: methods %K Amino Acid Sequence %K Animals %K Antibodies %K Antibody %K Binding Sites %K Cancer Vaccines %K Cancer Vaccines: genetics %K Cancer Vaccines: immunology %K Cancer Vaccines: pharmacology %K Cross Reactions %K DNA %K DNA: genetics %K DNA: immunology %K DNA: pharmacology %K Female %K Gangliosides %K Gangliosides: genetics %K Gangliosides: immunology %K Humans %K Immunoglobulin G %K Immunoglobulin G: biosynthesis %K Immunoglobulin G: immunology %K Immunotherapy %K Inbred BALB C %K Melanoma %K Melanoma: immunology %K Melanoma: therapy %K Mice %K Molecular Sequence Data %K Monoclonal %K Monoclonal: genetics %K Monoclonal: immunology %K Neuroblastoma %K Neuroblastoma: immunology %K Neuroblastoma: therapy %K Peptide Library %K Peptides %K Peptides: genetics %K Peptides: immunology %K SCID %K Vaccines %K Xenograft Model Antitumor Assays %X 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. %B Cancer Research %V 65 %P 3410–8 %8 apr %@ 7168458906 %G eng %U http://www.ncbi.nlm.nih.gov/pubmed/15833876 %R 10.1158/0008-5472.CAN-04-2164 %0 Journal Article %J The Journal of Steroid Biochemistry and Molecular Biology %D 2004 %T 2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor %A Pawel Grzywacz %A Lori A. Plum %A Wanda Sicinska %A Rafal R. Sicinski %A Jean M. Prahl %A Hector F. DeLuca %K Animals %K Binding Sites %K Calcitriol %K Female %K HL-60 Cells %K Humans %K Hydrocarbons %K Ligands %K Methane %K Mice %K Models, Molecular %K Rats %K Receptors, Calcitriol %X In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported. %B The Journal of Steroid Biochemistry and Molecular Biology %V 89-90 %P 13-7 %8 2004 May %G eng %N 1-5 %R 10.1016/j.jsbmb.2004.03.103