This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bera, T. K. Articles by Pastan, I. Search for Related Content PubMed PubMed Citation Articles by Bera, T. K. Articles by Pastan, I.

Pharmacokinetics and Antitumor Activity of a Bivalent Disulfide-stabilized Fv Immunotoxin with Improved Antigen Binding to erbB2

Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255

We have generated a stable bivalent Fv molecule [(dsFv)₂] of the anti-erbB2 monoclonal antibody e23 in which the V_H and V_L domains of the Fv are linked to each other by a disulfide bond and the two Fvs are connected by a 15-amino acid linker (T. K. Bera et al., J. Mol. Biol., 281: 475–483, 1998). The e23 (dsFv)₂ molecule is linked to a truncated form of Pseudomonas exotoxin (PE38) to generate a bivalent disulfide-stabilized immunotoxin e23 (dsFv)₂-PE38. Compared to the monovalent immunotoxin, the (dsFv)₂ immunotoxin showed greatly increased cytotoxicity to four cancer cell lines expressing low levels of erbB2 but not to four other cell lines with high erbB2 expression. e23 (dsFv)₂-PE38 was administered i.v. to mice, and its half-life was determined. The t_1/2 and t_1/2ß were 20 and 325 min, respectively, whereas the corresponding values for the monovalent dsFv immunotoxin were shorter, 6 and 52 min. The antitumor activities of the monovalent and bivalent immunotoxin were compared using mice bearing A431 tumors. Despite the fact that e23 (dsFv)₂-PE38 was 13-fold more active than e23 dsFv-PE38 on A431 cells in cell culture, its antitumor activity in mice was <2-fold that of the monovalent immunotoxin. These data show that a large increase in avidity does not always lead to an increase in cytotoxic activity. Furthermore, in one of the cases in which cytotoxic activity in vitro was greatly enhanced, there was only a small increase in antitumor activity.

This article has been cited by other articles:

				O. Tikhomirov and G. Carpenter Ligand-induced, p38-dependent Apoptosis in Cells Expressing High Levels of Epidermal Growth Factor Receptor and ErbB-2 J. Biol. Chem., March 26, 2004; 279(13): 12988 - 12996. [Abstract] [Full Text] [PDF]

				S. P. Cuadrado, M. d. C. Moreno Koch, C. F. Perez, L. M. Castejon Castan, C. P. Villalobos, M. J. Gonzalez Mateos, and C. L. Olmos Immunomodulation in Established Murine Tumors: Response and Survival Rate Enhancement by Blood Leukocyte-Augmenting Substance 236 (Cl-), a Novel Synthetic Compound Clin. Cancer Res., November 15, 2003; 9(15): 5776 - 5785. [Abstract] [Full Text] [PDF]

				T. K. Bera, J. Williams-Gould, R. Beers, P. Chowdhury, and I. Pastan Bivalent Disulfide-stabilized Fragment Variable Immunotoxin Directed against Mesotheliomas and Ovarian Cancer Mol. Cancer Ther., December 1, 2001; 1(2): 79 - 84. [Abstract] [Full Text] [PDF]

				D. W. Rusnak, K. Lackey, K. Affleck, E. R. Wood, K. J. Alligood, N. Rhodes, B. R. Keith, D. M. Murray, W. B. Knight, R. J. Mullin, et al. The Effects of the Novel, Reversible Epidermal Growth Factor Receptor/ErbB-2 Tyrosine Kinase Inhibitor, GW2016, on the Growth of Human Normal and Tumor-derived Cell Lines in Vitro and in Vivo Mol. Cancer Ther., December 1, 2001; 1(2): 85 - 94. [Abstract] [Full Text] [PDF]

				D. A. Vallera, D. W. Kuroki, A. Panoskaltsis-Mortari, D. J. Buchsbaum, B. E. Rogers, and B. R. Blazar Molecular modification of a recombinant anti-CD3epsilon -directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model Blood, August 1, 2000; 96(3): 1157 - 1165. [Abstract] [Full Text] [PDF]