| Autor: |
Yoram Reiter, Ulrich Brinkmann, Ira Pastan, Sun-Hee Jung, P. G. Kasprzyk, C. R. King, Byungkook Lee |
| Rok vydání: |
1994 |
| Předmět: |
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| Zdroj: |
Journal of Biological Chemistry. 269:18327-18331 |
| ISSN: |
0021-9258 |
| Popis: |
e23(dsFv)-PE38KDEL is a recombinant immunotoxin composed of the Fv region of anti-erbB2 monoclonal antibody e23 connected to a truncated form of Pseudomonas exotoxin (PE38KDEL), in which the inherently unstable Fv heterodimer (composed of VH and VL) is stabilized by a disulfide bond engineered between structurally conserved framework positions of VH and VL. We have now found that e23(dsFv)-PE38KDEL is considerably more cytotoxic to antigen-positive cell lines than the corresponding single-chain immunotoxin. The basis for the enhanced cytotoxic activity is that the e23 dsFv-immunotoxin binds to erbB2 with greater affinity than the single-chain counterpart. The dsFv-immunotoxin had 4-fold increased binding compared to the scFv and almost identical to the binding affinity of e23 Fab. e23(dsFv)-PE38KDEL was also considerably more stable at 37 degrees C than the single-chain immunotoxin. The therapeutic potential of the disulfide-stabilized immunotoxin was compared with its single-chain counterpart using two animal models of immunodeficient mice bearing subcutaneous tumor xenografts of human gastric tumor N87 cells or human A431 epidermoid carcinoma cells. The antitumor effect of e23(dsFv)-PE38KDEL was significantly better than that of the single-chain immunotoxin. e23(dsFv)-PE38KDEL caused complete regression of tumors at doses which caused no toxic effects in mice, whereas the single-chain immunotoxin did not cause complete regressions at the same doses. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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