Skip to main content

Advertisement

SpringerLink
Log in

ADAM17-overexpressing breast cancer cells selectively targeted by antibody–toxin conjugates

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

A disintegrin and metalloproteinase 17 (ADAM17) is significantly upregulated not only in malignant cells but also in the pro-inflammatory microenvironment of breast cancer. There, ADAM17 is critically involved in the processing of tumor-promoting proteins. Therefore, ADAM17 appears to be an attractive therapeutic target to address not only tumor cells but also the tumor-promoting environment. In a previous study, we generated a monoclonal anti-ADAM17 antibody (A300E). Although showing no complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity, the antibody was rapidly internalized by ADAM17-expressing cells and was able to transport a conjugated toxin into target cells. As a result, doxorubicin-coupled A300E or Pseudomonas exotoxin A-loaded A300E was able to kill ADAM17-expressing cells. This effect was strictly dependent on the presence of ADAM17 on the surface of target cells. As a proof of principle, both immunotoxins killed MDA-MB-231 breast cancer cells in an ADAM17-dependent manner. These data suggest that the use of anti-ADAM17 monoclonal antibodies as a carrier might be a promising new strategy for selective anti-cancer drug delivery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Black RA, Rauch CT, Kozlosky CJ et al (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385(6618):729–733

    Article  PubMed  CAS  Google Scholar 

  2. Scheller J, Chalaris A, Garbers C et al (2011) ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 32(8):380–387

    Article  PubMed  CAS  Google Scholar 

  3. Blanchot-Jossic F, Jarry A, Masson D et al (2005) Up-regulated expression of ADAM17 in human colon carcinoma: co-expression with EGFR in neoplastic and endothelial cells. J Pathol 207(2):156–163

    Article  PubMed  CAS  Google Scholar 

  4. Dijkstra A, Postma DS, Noordhoek JA et al (2009) Expression of ADAMs (“a disintegrin and metalloprotease”) in the human lung. Virchows Arch 454(4):441–449

    Article  PubMed  CAS  Google Scholar 

  5. Zheng X, Jiang F, Katakowski M et al (2011) ADAM17 promotes glioma cell malignant phenotype. Mol Carcinog 51(2):150–164

    Article  PubMed  Google Scholar 

  6. Wu K, Liao M, Liu B et al (2011) ADAM-17 over-expression in gallbladder carcinoma correlates with poor prognosis of patients. Med Oncol (Northwood, Lond, Engl) 28(2):475–480

    Article  CAS  Google Scholar 

  7. Gooz M (2010) ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol 45(2):146–169

    Article  PubMed  CAS  Google Scholar 

  8. Narita D, Seclaman E, Ilina R et al (2011) ADAM12 and ADAM17 gene expression in laser-capture microdissected and non-microdissected breast tumors. Pathol Oncol Res 17(2):375–385

    Article  PubMed  CAS  Google Scholar 

  9. McGowan PM, McKiernan E, Bolster F et al (2008) ADAM-17 predicts adverse outcome in patients with breast cancer. Ann Oncol 19(6):1075–1081

    Article  PubMed  CAS  Google Scholar 

  10. Zheng X, Jiang F, Katakowski M et al (2009) ADAM17 promotes breast cancer cell malignant phenotype through EGFR–PI3K–AKT activation. Cancer Biol Ther 8(11):1045–1054

    Article  PubMed  CAS  Google Scholar 

  11. Griffiths GL, Mattes MJ, Stein R et al (2003) Cure of SCID mice bearing human B-lymphoma xenografts by an anti-CD74 antibody-anthracycline drug conjugate. Clin Cancer Res 9(17):6567–6571

    PubMed  CAS  Google Scholar 

  12. Guin S, Ma Q, Padhye S et al (2011) Targeting acute hypoxic cancer cells by doxorubicin-immunoliposomes directed by monoclonal antibodies specific to RON receptor tyrosine kinase. Cancer Chemother Pharmacol 67(5):1073–1083

    Article  PubMed  CAS  Google Scholar 

  13. Kellner C, Bleeker WK, Lammerts van Bueren JJ et al (2011) Human kappa light chain targeted Pseudomonas exotoxin A—identifying human antibodies and Fab fragments with favorable characteristics for antibody-drug conjugate development. J Immunol Methods 371(1–2):122–133

    Article  PubMed  CAS  Google Scholar 

  14. Lorenzen I, Trad A, Grotzinger J (2011) Multimerisation of A disintegrin and metalloprotease protein-17 (ADAM17) is mediated by its EGF-like domain. Biochem Biophys Res Commun 415(2):330–336

    Article  PubMed  CAS  Google Scholar 

  15. Lorenzen I, Lokau J, Düsterhöft S et al (2012) The membrane-proximal domain of A disintegrin and metalloprotease 17 (ADAM17) is responsible for recognition of the interleukin-6 receptor and interleukin-1 receptor II. FEBS Lett 586(8):1093–1100

    Article  PubMed  CAS  Google Scholar 

  16. Trad A, Hedemann N, Shomali M et al (2011) Development of sandwich ELISA for detection and quantification of human and murine a disintegrin and metalloproteinase17. J Immunol Methods 371(1–2):91–96

    Article  PubMed  CAS  Google Scholar 

  17. Hu Z, Li J (2010) Natural killer cells are crucial for the efficacy of Icon (factor VII/human IgG1 Fc) immunotherapy in human tongue cancer. BMC Immunol 11:49

    Article  PubMed  Google Scholar 

  18. Tai YT, Dillon M, Song W et al (2008) Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 112(4):1329–1337

    Article  PubMed  CAS  Google Scholar 

  19. Gerber HP, Kung-Sutherland M, Stone I et al (2009) Potent antitumor activity of the anti-CD19 auristatin antibody drug conjugate hBU12-vcMMAE against rituximab-sensitive and -resistant lymphomas. Blood 113(18):4352–4361

    Article  PubMed  CAS  Google Scholar 

  20. Johansson S, Goldenberg DM, Griffiths GL et al (2006) Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody. AIDS (Lond, Engl) 20(15):1911–1915

    Article  CAS  Google Scholar 

  21. Sapra P, Stein R, Pickett J et al (2005) Anti-CD74 antibody-doxorubicin conjugate, IMMU-110, in a human multiple myeloma xenograft and in monkeys. Clin Cancer Res 11(14):5257–5264

    Article  PubMed  CAS  Google Scholar 

  22. Baumgart A, Seidl S, Vlachou P et al (2010) ADAM17 regulates epidermal growth factor receptor expression through the activation of Notch1 in non-small cell lung cancer. Cancer Res 70(13):5368–5378

    Article  PubMed  CAS  Google Scholar 

  23. Satoh M, Iwasaka J, Nakamura M et al (2004) Increased expression of tumor necrosis factor-α converting enzyme and tumor necrosis factor-α in peripheral blood mononuclear cells in patients with advanced congestive heart failure. Eur J Heart Fail 6(7):869–875. doi:10.1016/j.ejheart.2004.02.007

    PubMed  CAS  Google Scholar 

  24. Shimoda Y, Satoh M, Nakamura M et al (2005) Activated tumour necrosis factor-alpha shedding process is associated with in-hospital complication in patients with acute myocardial infarction. Clin Sci 108(4):339–347. doi:10.1042/cs20040229

    Article  PubMed  CAS  Google Scholar 

  25. Arribas J, Esselens C (2009) ADAM17 as a therapeutic target in multiple diseases. Curr Pharm Des 15(20):2319–2335

    Article  PubMed  CAS  Google Scholar 

  26. Maretzky T, Evers A, Zhou W et al (2011) Migration of growth factor-stimulated epithelial and endothelial cells depends on EGFR transactivation by ADAM17. Nat Commun 2:229

    Article  PubMed  Google Scholar 

  27. Binyamin L, Alpaugh RK, Hughes TL et al (2008) Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy. J Immunol 180(9):6392–6401

    PubMed  CAS  Google Scholar 

  28. Saleh MN, Sugarman S, Murray J et al (2000) Phase I trial of the anti-Lewis Y drug immunoconjugate BR96-doxorubicin in patients with lewis Y-expressing epithelial tumors. J Clin Oncol 18(11):2282–2292

    PubMed  CAS  Google Scholar 

  29. Muldoon LL, Neuwelt EA (2003) BR96–DOX immunoconjugate targeting of chemotherapy in brain tumor models. J Neurooncol 65(1):49–62

    Article  PubMed  Google Scholar 

  30. Inoh K, Muramatsu H, Torii S et al (2006) Doxorubicin-conjugated anti-midkine monoclonal antibody as a potential anti-tumor drug. Jpn J Clin Oncol 36(4):207–211

    Article  PubMed  Google Scholar 

  31. Gualberto A (2012) Brentuximab vedotin (SGN-35), an antibody-drug conjugate for the treatment of CD30-positive malignancies. Expert Opin Investig Drugs 21(2):205–216

    Article  PubMed  CAS  Google Scholar 

  32. Fanale MA, Forero-Torres A, Rosenblatt JD et al (2012) A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res 18(1):248–255

    Article  PubMed  CAS  Google Scholar 

  33. Kreitman RJ, Pastan I (2011) Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res 17(20):6398–6405

    Article  PubMed  CAS  Google Scholar 

  34. Kreitman RJ, Pastan I (1998) Accumulation of a recombinant immunotoxin in a tumor in vivo: fewer than 1,000 molecules per cell are sufficient for complete responses. Cancer Res 58(5):968–975

    PubMed  CAS  Google Scholar 

  35. Klimka A, Barth S, Matthey B et al (1999) An anti-CD30 single-chain Fv selected by phage display and fused to Pseudomonas exotoxin A (Ki-4(scFv)-ETA′) is a potent immunotoxin against a Hodgkin-derived cell line. Br J Cancer 80(8):1214–1222

    Article  PubMed  CAS  Google Scholar 

  36. Alderson RF, Kreitman RJ, Chen T et al (2009) CAT-8015: a second-generation pseudomonas exotoxin A-based immunotherapy targeting CD22-expressing hematologic malignancies. Clin Cancer Res 15(3):832–839

    Article  PubMed  CAS  Google Scholar 

  37. Kreitman RJ, Tallman MS, Robak T et al (2012) Phase I trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox (CAT-8015 or HA22) in patients with hairy cell leukemia. J Clin Oncol 30(15):1822–1828

    Article  PubMed  CAS  Google Scholar 

  38. Pastan I, Hassan R, FitzGerald DJ et al (2007) Immunotoxin treatment of cancer*. Annu Rev Med 58(1):221–237. doi:10.1146/annurev.med.58.070605.115320

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Holger Kalthoff (UKSH Kiel, Germany) for providing the MDA-MB-231 breast cancer cell line and Panc89 pancreatic cancer cell line. This study has been supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB 877, A6, Z3) and the cluster of excellence “Inflammation at Interfaces.” Kosuke Yamamoto was supported by a postdoctoral fellowship from the German Academic Exchange Service (DAAD).

Conflict of interest

The authors declare they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Biochemistry, Christian-Albrechts-University of Kiel, Olshausenstr. 40, 24098, Kiel, Germany

    Ahmad Trad, Mohammad Shomali, Nina Hedemann, Kosuke Yamamoto, André Mauermann, Christine Desel, Inken Lorenzen, Hilmar Lemke, Stefan Rose-John & Joachim Grötzinger

  2. Laboratory of Immunotherapy, Department I of Internal Medicine, University Clinic of Cologne, Cologne, Germany

    Hinrich P. Hansen

  3. Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, Christian-Albrechts-University, Kiel, Germany

    Matthias Peipp & Katja Klausz

Authors
  1. Ahmad Trad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hinrich P. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammad Shomali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthias Peipp
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katja Klausz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nina Hedemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kosuke Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. André Mauermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christine Desel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Inken Lorenzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hilmar Lemke
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Stefan Rose-John
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Joachim Grötzinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joachim Grötzinger.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 401 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trad, A., Hansen, H.P., Shomali, M. et al. ADAM17-overexpressing breast cancer cells selectively targeted by antibody–toxin conjugates. Cancer Immunol Immunother 62, 411–421 (2013). https://doi.org/10.1007/s00262-012-1346-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-012-1346-x

Keywords

Search

Navigation