Isolation and structural analysis of peptide mimotopes for the disialoganglioside GD2, a neuroblastoma tumor antigen.
The disialoganglioside GalAcbeta1-4(NeuAcalpha2-8NeuAcalpha2-3)Galbeta1-4Glcbeta1-1Cer (GD2) is expressed on various tumors, including neuroblastoma, and was defined as a relevant tumor antigen. The monoclonal anti-GD2 antibody 14.18 is widely used for diagnostic purposes in neuroblastoma, and in its mouse/human chimeric form (ch14.18) now enters passive immunotherapeutic regimens in phase II clinical trials. This study aimed to generate structural mimics of the 14.18 epitope of GD2. Therefore, we used the ch14.18 antibody for selecting immunoreactive GD2 peptide mimotopes from a decamer phage display library. In all, 13 GD2 peptide mimics could be determined by biopanning and their specificity was demonstrated by exclusive recognition by the ch14.18 antibody. Furthermore, their nature of being GD2 mimics and their degree of mimicry was confirmed by competition with the natural antigen. When performing a comparative visualization of the GD2 epitope and selected mimotopes using a three-dimensional computer modeling system (BALLView), we demonstrated fitting of the GD2 molecule and the mimotopes in the antigen-binding pouch of a GD2 specific antibody. Moreover, the computer modeling argued for optimal affinity of the GD2 mimotopes. We thus provide evidence that the generation of GD2 peptide mimotopes is successful when using the neuroblastoma antibody ch14.18 for selection, and that this approach might offer a tool to develop a vaccination strategy against this malignant pediatric tumor.
Förster-Waldl
Elisabeth
E
Department of Pediatrics and Juvenile Medicine, Medical University of Vienna, Austria.
Riemer
Angelika B
AB
Dehof
Anna Katharina
AK
Neumann
Dirk
D
Brämswig
Kira
K
Boltz-Nitulescu
George
G
Pehamberger
Hubert
H
Zielinski
Christoph C
CC
Scheiner
Otto
O
Pollak
Arnold
A
Lode
Holger
H
Jensen-Jarolim
Erika
E
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000737:chemistry* / Q000276:immunology / Q000302:isolation & purification; D001667:Binding, Competitive; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification; D005732:Gangliosides / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D051379:Mice; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000276:immunology*; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000276:immunology* / Q000302:isolation & purification; D011487:Protein Conformation
D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D000939:Epitopes; D005732:Gangliosides; D007140:Immunoglobulin Fab Fragments; D019151:Peptide Library; D010455:Peptides; C019403:ganglioside, GD2; C112746:dinutuximab