Comparative immunogenicity and structural analysis of epitopes of different bacterial L-asparaginasesReport as inadecuate




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BMC Cancer

, 16:89

Experimental therapeutics and drug development

Abstract

BackgroundE.coli type II L-asparaginase is widely used for treatment of acute lymphoblastic leukemia. However, serious side effects such as allergic or hypersensitivity reactions are common for L-asparaginase treatment. Methods for minimizing immune response on L-asparaginase treatment in human include bioengeneering of less immunogenic version of the enzyme or utilizing the homologous enzymes of different origin. To rationalize these approaches we compared immunogenicity of L-asparaginases from five bacterial organisms and performed sequence-structure analysis of the presumable epitope regions.

MethodsIgG and IgM immune response in C57B16 mice after immunization with Wollinella succinogenes type II WsA, Yersinia pseudotuberculosis type II YpA, Erwinia carotovora type II EwA, and Rhodospirillum rubrum type I RrA and Escherichia coli type II EcA L-asparaginases was evaluated using standard ELISA method. The comparative bioinformatics analysis of structure and sequence of the bacterial L-asparaginases presumable epitope regions was performed.

ResultsWe showed different immunogenic properties of five studied L-asparaginases and confirmed the possibility of replacement of EcA with L-asparaginase from different origin as a second-line treatment. Studied L-asparaginases might be placed in the following order based on the immunogenicity level: YpA > RrA, WsA ≥ EwA > EcA. Most significant cross-immunogenicity was shown between EcA and YpA. We propose that a long N-terminus of YpA enzyme enriched with charged aminoacids and tryptophan could be a reason of higher immunogenicity of YpA in comparison with other considered enzymes. Although the recognized structural and sequence differences in putative epitope regions among five considered L-asparaginases does not fully explain experimental observation of the immunogenicity of the enzymes, the performed analysis set the foundation for further research in this direction.

ConclusionsThe performed studies showed different immunogenic properties of L-asparaginases and confirmed the possibility of replacement of EcA with L-asparaginase from different origin. The preferable enzymes for the second line treatment are WsA, RrA, or EwA.

KeywordsL-asparaginase Immunogenicity Epitope AbbreviationsEcAEscherichia coli L-asparaginase

WsAWollinella succinogenes L-asparaginase

EwAErwinia carotovora L-asparaginase

YpAYersinia pseudotuberculosis L-asparaginase

RrARhodospirillum rubrum L-asparaginase

PEGpolyethylene glycol

IgGimmunoglobulin G

IgMimmunoglobulin M

ELISAenzyme-linked immunosorbent assay

Electronic supplementary materialThe online version of this article doi:10.1186-s12885-016-2125-4 contains supplementary material, which is available to authorized users.

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Author: Vadim S. Pokrovsky - Marat D. Kazanov - Ilya N. Dyakov - Marina V. Pokrovskaya - Svetlana S. Aleksandrova

Source: https://link.springer.com/







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