A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity.
Blood
; 113(16): 3792-800, 2009 Apr 16.
Article
em En
| MEDLINE
| ID: mdl-18988862
ABSTRACT
Immunotoxins based on Pseudomonas exotoxin A (PE) are promising anticancer agents that combine a variable fragment (Fv) from an antibody to a tumor-associated antigen with a 38-kDa fragment of PE (PE38). The intoxication pathway of PE immunotoxins involves receptor-mediated internalization and trafficking through endosomes/lysosomes, during which the immunotoxin undergoes important proteolytic processing steps but must otherwise remain intact for eventual transport to the cytosol. We have investigated the proteolytic susceptibility of PE38 immunotoxins to lysosomal proteases and found that cleavage clusters within a limited segment of PE38. We subsequently generated mutants containing deletions in this region using HA22, an anti-CD22 Fv-PE38 immunotoxin currently undergoing clinical trials for B-cell malignancies. One mutant, HA22-LR, lacks all identified cleavage sites, is resistant to lysosomal degradation, and retains excellent biologic activity. HA22-LR killed chronic lymphocytic leukemia cells more potently and uniformly than HA22, suggesting that lysosomal protease digestion may limit immunotoxin efficacy unless the susceptible domain is eliminated. Remarkably, mice tolerated doses of HA22-LR at least 10-fold higher than lethal doses of HA22, and these higher doses exhibited markedly enhanced antitumor activity. We conclude that HA22-LR advances the therapeutic efficacy of HA22 by using an approach that may be applicable to other PE-based immunotoxins.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Toxinas Bacterianas
/
Região Variável de Imunoglobulina
/
Leucemia Linfocítica Crônica de Células B
/
Imunotoxinas
/
ADP Ribose Transferases
/
Ensaios Antitumorais Modelo de Xenoenxerto
/
Fatores de Virulência
/
Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico
/
Exotoxinas
/
Anticorpos Monoclonais
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article