Removal of B-cell epitopes for decreasing immunogenicity in recombinant immunotoxin against B-cell malignancies.
J BUON
; 21(6): 1374-1378, 2016.
Article
em En
| MEDLINE
| ID: mdl-28039694
ABSTRACT
Recombinant immunotoxin HA22, composed of an anti- CD22 Fv fragment fused to PE38, a truncated portion of Pseudomonas Exotoxin A (PE), has been developed for targeted treatment of various B-cell malignancies. As a foreign, internalized macromolecule, PE38 often induces lysosomal degradation and neutralizing antibodies to limit the efficacy of treating B-cell malignancies. The region of PE38 containing lysosomal protease cleavage sites deleted, leaving only furin processing site. The resulting immunotoxin HA22-LR (lysosome resistant) retains excellent biologic activity and removes immunogenic epitopes as an additional benefit. Another approach for avoiding immunogenicity is to identify B-cell epitopes and remove them by mutagenesis. Previously, to determine B-cell epitopes on PE38, murine Ab as a model, 7 major mouse-specific B-cell epitope groups with 13 subgroups were identified and located through a series of point mutations. Two new mutants, HA22-8X and HA22-LR-8X, were prepared, containing 8 epitope-silencing mutations which greatly reduced immunogenicity in mice. Later, by phage-display assay, human Fvs against PE toxin were isolated and human-specific B-cell epitopes were located by alanine scanning mutagenesis. HA22-LR as a scaffold, HA22-LR-LO10 with 7 point mutations was constructed, has low reactivity with human antisera, yet has high cytotoxic and antitumor activity. In this review, theoretical aspects and experimental evidence for the removal of B-cell epitope is discussed.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Recombinantes
/
Linfócitos B
/
Imunotoxinas
/
Linfócitos do Interstício Tumoral
/
Epitopos de Linfócito B
/
Neoplasias Hematológicas
/
Imunoterapia
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article