Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Suppression of metastasis formation by a recombinant single chain antibody-toxin targeted to full-length and oncogenic variant EGF receptors

Oncogene volume 18, pages 1711–1721 (1999)Cite this article

Abstract

Cytotoxic strategies which are directed to tumor-associated antigens might be most beneficial for cancer patients with minimal tumor load such as in an adjuvant setting after initial therapy. We have recently described a highly potent single chain antibody-toxin, scFv(14E1)-ETA, which consists of the variable domains of the antibody 14E1 genetically fused to a truncated form of Pseudomonas exotoxin A. ScFv(14E1)-ETA specifically recognizes the human epidermal growth factor receptor (EGFR) and the oncogenically activated receptor variant EGFRvIII, which have been implicated in the development of various human malignancies. Here we have investigated the antimetastatic activity of bacterially expressed scFv(14E1)-ETA and its disulfide-stabilized derivative ds-scFv(14E1)-ETA in a novel model for disseminated disease which is based on murine renal carcinoma cells subsequently transfected with the E. coli β-galactosidase gene, and human full-length or variant EGFR cDNAs. Intravenous injection of these Renca-lacZ/EGFR and Renca-lacZ/EGFRvIII cells in syngenic Balb/c mice led to the formation of pulmonary metastases which were readily detectable upon excision of the lungs and X-gal staining. Systemic treatment of mice with scFv(14E1)-ETA resulted in the complete suppression of Renca-lacZ/EGFRvIII metastasis formation and drastically reduced the number of pulmonary Renca-lacZ/EGFR tumor nodules. The ds-scFv(14E1)-ETA derivative where the antibody variable regions are connected by an artificial disulfide bond displayed improved thermal stability at physiological temperature but due to reduced cytotoxic activity was less potent than the original scFv(14E1)-ETA in metastasis suppression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 6
Figure 5
Figure 7
Figure 8

Similar content being viewed by others

References

  • Altenschmidt U, Schmidt M, Groner B and Wels W. . 1997 Int. J. Cancer 73: 117–124.

  • Fan Z and Mendelsohn J. . 1998 Curr. Opin. Oncol. 10: 67–73.

  • Garcia de Palazzo IE, Adams GP, Sundareshan P, Wong AJ, Testa JR, Bigner DD and Weiner LM. . 1993 Cancer Res. 53: 3217–3220.

  • Glockshuber R, Malia M, Pfitzinger I and Plückthun A. . 1990 Biochemistry 29: 1362–1367.

  • Groner B, Wick B, Jeschke M, Fiebig HH, Dengler W, Runau T, Mihatsch M, Kahl R, Schmidt M, Wels W and Stöcklin E. . 1997 Int. J. Cancer 70: 682–687.

  • Gullick WJ. . 1991 Br. Med. Bull 47: 87–98.

  • Gullick WJ, Downward J and Waterfield MD. . 1985 EMBO J. 4: 2869–2877.

  • Hills D, Rowlinson-Busza G and Gullick WJ. . 1995 Int. J. Cancer 63: 537–543.

  • Humphrey PA, Wong AJ, Vogelstein B, Friedman HS, Werner MH, Bigner DD and Bigner SH. . 1988 Cancer Res. 48: 2231–2238.

  • Hwang J, Fitzgerald DJ, Adhya S and Pastan I. . 1987 Cell 48: 129–136.

  • Kabat EA, Wu TT, Perry HM, Gottesman KS and Foeller C. . 1991 Sequences of proteins of immunological interest, 5th edn. U.S. Department of Health and Human Services, National Institutes of Health.

    Google Scholar 

  • Lorimer IAJ, Kepplerhafkemeyer A, Beers RA, Pegram CN, Bigner DD and Pastan I. . 1996 Proc. Natl. Acad. Sci. USA 93: 14815–14820.

  • Luo D, Mah N, Krantz M, Wilde K, Wishart D, Zhang Y, Jacobs F and Martin L. . 1995 J. Biochem. 118: 825–831.

  • Maurer-Gebhard M, Schmidt M, Azemar M, Altenschmidt U, Stöcklin E, Wels W and Groner B. . 1998 Cancer Res. 58: 2661–2666.

  • Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Biegel JA, Hayes RL and Wong AJ. . 1995 Cancer Res. 55: 5536–5539.

  • Murphy GP and Hrushesky WJ. . 1973 J. Natl. Cancer Inst. 50: 1013–1025.

  • Ogata M, Fryling CM, Pastan I and FitzGerald DJ. . 1992 J. Biol. Chem. 267: 25396–25401.

  • Pai LH, Wittes R, Setser A, Willingham MC and Pastan I. . 1996 Nature Medicine 2: 350–353.

  • Pantel K and Riethmüller G. . 1996 Curr. Top Microbiol. Immunol. 213: 1–18.

  • Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR and Riethmüller G. . 1993 J. Natl. Cancer Inst. 85: 1419–1424.

  • Pastan I and FitzGerald D. . 1991 Science 254: 1173–1177.

  • Reiter Y, Brinkmann U, Lee B and Pastan I. . 1996 Nature Biotechnology 14: 1239–1245.

  • Schmidt M, Reiser P, Hills D, Gullick WJ and Wels W. . 1998 Int. J. Cancer 75: 878–884.

  • Schmidt M, Vakalopoulou E, Schneider DW and Wels W. . 1997 Br. J. Cancer 75: 1575–1584.

  • Spyridonidis A, Schmidt M, Bernhardt W, Papadimitriou A, Azemar M, Wels W, Groner B and Henschler R. . 1998 Blood 91: 1820–1827.

  • Sugawa N, Ekstrand AJ, James CD and Collins VP. . 1990 Proc. Natl. Acad. Sci. USA 87: 8602–8606.

  • Wels W, Beerli R, Hellmann P, Schmidt M, Marte BM, Kornilova ES, Hekele A, Mendelsohn J, Groner B and Hynes NE. . 1995 Int. J. Cancer 60: 137–144.

  • Wels W, Groner B and Hynes NE. . 1996 Curr. Top Microbiol. Immunol. 213: 113–128.

  • Wels W, Harwerth IM, Mueller M, Groner B and Hynes NE. . 1992 Cancer Res. 52: 6310–6317.

  • Wikstrand CJ, Hale LP, Batra SK, Hill ML, Humphrey PA, Kurpad SN, McLendon RE, Moscatello D, Pegram CN, Reist CJ, Traweek ST, Wong AJ, Zalutsky MR and Bigner DD. . 1995 Cancer Res. 55: 3140–3148.

  • Yamazaki H, Ohba Y, Tamaoki N and Shibuya M. . 1990 Jpn. J. Cancer Res. 81: 773–779.

  • Young NM, MacKenzie CR, Narang SA, Oomen RP and Baenziger JE. . 1995 FEBS Lett. 377: 135–139.

Download references

Acknowledgements

We thank Dr WJ Gullick, ICRF London, for plasmids pLTR-EGFR, pLTR-EGFRvIII and DH-EΔ801-P cells. This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (SFB 364-C1).

Author information

Author notes

  1. Mathias Schmidt

    Present address: The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, 77030, USA

Authors and Affiliations

  1. Institute for Experimental Cancer Research, Tumor Biology Center, Breisacher Strasse 117, Freiburg, D-79106, Germany

    Mathias Schmidt, Martina Maurer-Gebhard, Bernd Groner, Gesa Brochmann-Santos & Winfried Wels

  2. Georg-Speyer-Haus Institute for Biomedical Research, Paul-Ehrlich-Strasse 42-44, Frankfurt, Main, D-60596, Germany

    Bernd Groner & Winfried Wels

  3. Department of Pathology, University of Freiburg, Albertstrasse 19, Freiburg, D-79104, Germany

    Gabriele Köhler

Authors
  1. Mathias Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Maurer-Gebhard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bernd Groner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gabriele Köhler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gesa Brochmann-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Winfried Wels
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmidt, M., Maurer-Gebhard, M., Groner, B. et al. Suppression of metastasis formation by a recombinant single chain antibody-toxin targeted to full-length and oncogenic variant EGF receptors. Oncogene 18, 1711–1721 (1999). https://doi.org/10.1038/sj.onc.1202489

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202489

Keywords

This article is cited by

Search

Advanced search

Quick links