Recombinant immunotoxin containing a disulfide-stabilized Fv directed at erbB2 that does not require proteolytic activation

Biochemistry
C T Kuan, I Pastan

Abstract

PE35/e23(dsFv)KDEL is a recombinant immunotoxin composed of a recombinant form of Pseudomonas exotoxin that does not need proteolytic activation and a disulfide-stabilized Fv fragment of the anti-erbB2 monoclonal antibody e23. In this molecule, the variable heavy (V H) domain is inserted near the carboxyl terminus of PE at position 607 and the variable light (V L) domain is connected to the V H domain by a disulfide bond engineered into the framework region. The disulfide bond forms between cysteines introduced at position 44 of V H and position 99 of V L [Reiter et al. (1994) J. Biol. Chem. 269, 18327-18331]. In contrast to other PE-derived Fv fusion proteins, this type of recombinant toxin does not need proteolytic activation of the toxin domain. PE35/e23(dsFv)KDEL is very cytotoxic toward erbB2 antigen-expressing N87 cells (IC50 = 0.8 ng/mL) despite the fact that it binds to the erbB2 protein only 25% as well as e23(dsFv)PE38KDEL, in which the dsFv moiety is located at the amino terminus of the toxin. The lower binding affinity is probably due to interference by domain III of PE with the amino terminus of e23(V H), possibly where the antigen binding sites are located. Nevertheless, the specificity of immunotoxin is still ret...Continue Reading

References

Jan 1, 1992·Annual Review of Biochemistry·I PastanD J FitzGerald
May 5, 1986·Journal of Molecular Biology·F W Studier, B A Moffatt
Apr 1, 1993·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M L GrossbardC L Epstein

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Citations

Aug 1, 2000·Pharmaceutical Science & Technology Today·U B Nielsen, J D Marks
Oct 4, 2006·BMC Immunology·Ulrik B NielsenJames D Marks
Oct 12, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Y SatoY Niitsu

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