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Regression of Cutaneous Tumor Lesions in Patients Intratumorally Injected with a Recombinant Single-chain Antibody-toxin Targeted to ErbB2/HER2

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Abstract

ScFv(FRP5)-ETA is a recombinant single-chain antibody-toxin with binding specificity for ErbB2/HER2. Previously potent antitumoral activity of the molecule against ErbB2 overexpressing tumor cells was demonstrated in vitro and in animal models. Here we report on the first application of scFv(FRP5)-ETA in human cancer patients summarizing case reports collected in four different clinical centers. Eleven patients suffering from metastatic breast and colorectal cancers and from malignant melanoma were treated on a compassionate-use basis by intratumoral injection of scFv(FRP5)-ETA into cutaneous lesions once daily for 7–10 days. Total daily doses ranged from 60 to 900 µg, and total doses per treatment cycle ranged from 0.6 to 6.0 mg. Treatment caused injected tumors to shrink in six of the 10 cases evaluated (60%). Complete regression of injected tumor nodules was accomplished in four patients (40%) and partial reduction in tumor size in another two patients (20%). Adverse reactions were restricted to local symptoms such as pain and inflammation at injection sites which were fully reversible. Only in one patient treated at the highest daily doses systemic liver toxicity of grade 2 was observed and treatment was discontinued on day 7. No hematologic, renal, and/or cardiovascular toxicities were noted. Our results demonstrate that local therapy with scFv(FRP5)-ETA can be effective against ErbB2 expressing tumors justifying further clinical development of this reagent.

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References

  1. Olayioye MA, Neve RM, Lane HA, Hynes NE: The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19: 3159-3167, 2000

    Google Scholar 

  2. Yarden Y, Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2: 127-137, 2001

    Google Scholar 

  3. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney Jr DW, Leahy DJ: Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421: 756-760, 2003

    Google Scholar 

  4. Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Kofler M, Jorissen RN, Nice EC, Burgess AW, Ward CW: The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol Cell 11: 495-505, 2003

    Google Scholar 

  5. Mendelsohn J, Baselga J: The EGF receptor family as targets for cancer therapy. Oncogene 19: 6550-6565, 2000

    Google Scholar 

  6. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20: 719-726, 2002

    Google Scholar 

  7. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-792, 2001

    Google Scholar 

  8. Kreitman RJ: Recombinant toxins for the treatment of cancer. Curr Opin Mol Ther 5: 44-51, 2003

    Google Scholar 

  9. Wels W, Harwerth IM, Mueller M, Groner B, Hynes NE: Selective inhibition of tumor cell growth by a recombinant single-chain antibody-toxin specific for the erbB-2 receptor. Cancer Res 52: 6310-6317, 1992

    Google Scholar 

  10. Harwerth IM, Wels W, Marte BM, Hynes NE: Monoclonal antibodies against the extracellular domain of the erbB-2 receptor function as partial ligand agonists. J Biol Chem 267: 15160-15167, 1992

    Google Scholar 

  11. Iglewski BH, Liu PV, Kabat D: Mechanism of action of Pseudomonas aeruginosa exotoxin Aiadenosine diphosphateribosylation of mammalian elongation factor 2 in vitro and in vivo. Infect Immun 15: 138-144, 1977

    Google Scholar 

  12. Keppler-Hafkemeyer A, Kreitman RJ, Pastan I: Apoptosis induced by immunotoxins used in the treatment of hematologic malignancies. Int J Cancer 87: 86-94, 2000

    Google Scholar 

  13. Schmidt M, McWatters A, White RA, Groner B, Wels W, Fan Z, Bast RC: Synergistic interaction between an anti-p185HER-2 Pseudomonas exotoxin fusion protein [scFv(FRP5)-ETA] and ionizing radiation for inhibiting growth of ovarian cancer cells that overexpress HER-2. Gynecol Oncol 80: 145-155, 2001

    Google Scholar 

  14. Spyridonidis A, Schmidt M, Bernhardt W, Papadimitriou A, Azemar M, Wels W, Groner B, Henschler R: Purging of mammary carcinoma cells during ex vivo culture of CD34+ hematopoietic progenitor cells with recombinant immunotoxins. Blood 91: 1820-1827, 1998

    Google Scholar 

  15. Wels W, Beerli R, Hellmann P, Schmidt M, Marte BM, Kornilova ES, Hekele A, Mendelsohn J, Groner B, Hynes NE: EGF receptor and p185erbB-2-specific single-chain antibody toxins differ in their cell-killing activity on tumor cells expressing both receptor proteins. Int J Cancer 60: 137-144, 1995

    Google Scholar 

  16. Azemar M, Schmidt M, Arlt F, Kennel P, Brandt B, Papadimitriou A, Groner B, Wels W: Recombinant antibody toxins specific for ErbB2 and EGF receptor inhibit the in vitro growth of human head and neck cancer cells and cause rapid tumor regression in vivo. Int J Cancer 86: 269-275, 2000

    Google Scholar 

  17. Wang L, Liu B, Schmidt M, Lu Y, Wels W, Fan Z: Antitumor effect of an HER2-specific antibody-toxin fusion protein on human prostate cancer cells. Prostate 47: 21-28, 2001

    Google Scholar 

  18. Wels W, Moritz D, Schmidt M, Jeschke M, Hynes NE, Groner B: Biotechnological and gene therapeutic strategies in cancer Treatment. Gene 159: 73-80, 1995

    Google Scholar 

  19. Altenschmidt U, Schmidt M, Groner B, Wels W: Targeted therapy of schwannoma cells in immunocompetent rats with an erbB2-specific antibody-toxin. Int J Cancer 73: 117-124, 1997

    Google Scholar 

  20. Maurer-Gebhard M, Schmidt M, Azemar M, Altenschmidt U, Stocklin E, Wels W, Groner B: Systemic treatment with a recombinant erbB-2 receptor-specific tumor toxin efficiently reduces pulmonary metastases in mice injected with genetically modified carcinoma cells. Cancer Res 58: 2661-2666, 1998

    Google Scholar 

  21. Kreitman RJ, Wilson WH, White JD, Stetler-Stevenson M, Jaffe ES, Giardina S, Waldmann TA, Pastan I: Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J Clin Oncol 18: 1622-1636, 2000

    Google Scholar 

  22. Kreitman RJ, Wilson WH, Bergeron K, Raggio M, Stetler-Stevenson M, FitzGerald DJ, Pastan I: Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med 345: 241-247, 2001

    Google Scholar 

  23. Pai LH, Wittes R, Setser A, Willingham MC, Pastan I: Treatment of advanced solid tumors with immunotoxin LMB-1: an antibody linked to Pseudomonas exotoxin. Nat Med 2: 350-353, 1996

    Google Scholar 

  24. Press MF, Cordon-Cardo C, Slamon DJ: Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 5: 953-962, 1990

    Google Scholar 

  25. Hynes NE, Stern DF: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198: 165-184, 1994

    Google Scholar 

  26. Reiter Y, Brinkmann U, Jung SH, Lee B, Kasprzyk PG, King CR, Pastan I: Improved binding and antitumor activity of a recombinant anti-erbB2 immunotoxin by disulfide stabilization of the Fv fragment. J Biol Chem 269: 18327-18331, 1994

    Google Scholar 

  27. Pai-Scherf LH, Villa J, Pearson D, Watson T, Liu E, Willingham MC, Pastan I: Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor. Clin Cancer Res 5: 2311-2315, 1999

    Google Scholar 

  28. King CR, Fischer PH, Rando RF, Pastan I: The performance of e23(Fv)PEs, recombinant toxins targeting the erbB-2 protein. Semin Cancer Biol 7: 79-86, 1996

    Google Scholar 

  29. Tsutsumi Y, Onda M, Nagata S, Lee B, Kreitman RJ, Pastan I: Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity. Proc Natl Acad Sci USA 97: 8548-8553, 2000

    Google Scholar 

  30. Onda M, Willingham M, Wang QC, Kreitman RJ, Tsutsumi Y, Nagata S, Pastan I: Inhibition of TNF-alpha produced by Kupffer cells protects against the nonspecific liver toxicity of immunotoxin anti-Tac(Fv)-PE38, LMB-2. J Immunol 165: 7150-7156, 2000

    Google Scholar 

  31. Onda M, Nagata S, Tsutsumi Y, Vincent JJ, Wang Q, Kreitman RJ, Lee B, Pastan I: Lowering the isoelectric point of the Fv portion of recombinant immunotoxins leads to decreased nonspecific animal toxicity without affecting antitumor activity. Cancer Res 61: 5070-5077, 2001

    Google Scholar 

  32. Yip YL, Ward RL: Anti-ErbB-2 monoclonal antibodies and ErbB-2-directed vaccines. Cancer Immunol Immunother 50: 569-587, 2002

    Google Scholar 

  33. Keefe DL: Trastuzumab-associated cardiotoxicity. Cancer 95: 1592-1600, 2002

    Google Scholar 

  34. Gerstmayer B, Altenschmidt U, Hoffmann M, Wels W: Costimulation of T cell proliferation by a chimeric B7-2 antibody fusion protein specifically targeted to cells expressing the erbB2 proto-oncogene. J Immunol 158: 4584-4590, 1997

    Google Scholar 

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Author notes

  1. Mathias Schmidt

    Present address: Department Oncology Research, Altana Pharma AG, Konstanz, Germany

Authors and Affiliations

  1. Tumor Biology Center, Freiburg, Germany

    Marc Azemar, Mathias Schmidt, Klaus Mross & Clemens Unger

  2. Department of Obstetrics and Gynecology, Heinrich-Heine-University, Düsseldorf, Germany

    Sirus Djahansouzi & Peter Dall

  3. Hämatologie-Onkologie, Medizinische Klinik II, Krankenhaus Nordwest, Germany

    Elke Jäger

  4. Department of Gynecology and Obstetrics, School of Medicine, Johann Wolfgang Goethe-University, Germany

    Christine Solbach & Gunter von Minckwitz

  5. Department Oncology Research, Altana Pharma AG, Konstanz, Germany

    Bernd Groner & Winfried S. Wels

  6. Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt am Main, Germany

    Alexander B. Maurer

  7. G2M Cancer Drugs AG, Frankfurt am Main, Germany

    Alexander B. Maurer

Authors
  1. Marc Azemar
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Azemar, M., Djahansouzi, S., Jäger, E. et al. Regression of Cutaneous Tumor Lesions in Patients Intratumorally Injected with a Recombinant Single-chain Antibody-toxin Targeted to ErbB2/HER2. Breast Cancer Res Treat 82, 155–164 (2003). https://doi.org/10.1023/B:BREA.0000004371.48757.19

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  • DOI: https://doi.org/10.1023/B:BREA.0000004371.48757.19

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