Der Onkologe

, 17:539

Monoklonale Antikörper in der Therapie von Tumorerkrankungen

CME Weiterbildung · Zertifizierte Fortbildung

Zusammenfassung

Monoklonale Antikörper (Mab) sind industriell hergestellte Immunglobuline, die sich gegen ein bestimmtes Epitop richten. In der Therapie maligner Erkrankungen spielen sie eine zunehmende Rolle. Sie hemmen das Tumorwachstum, indem sie Rezeptoren blockieren und die Signaltransduktion verhindern oder das körpereigene Immunsystem unterstützen und sich gegen vom Tumor produzierte Faktoren richten. Darüber hinaus können sie als konjugierte Antikörper, d. h. gebunden an radioaktive Isotope oder Chemotherapeutika, zum Einsatz kommen. Das Zielmolekül charakterisiert neben der Wirkung auch die Nebenwirkungen des eingesetzten Mab. Generell kann es aufgrund der immunmodulatorischen Eigenschaften der Antikörper zu Hypersensitivitätsreaktionen, Immunsuppression, Immunstimulation und Autoimmunität kommen. In Deutschland sind derzeit 8 unkonjugierte (Rituximab, Cetuximab, Panitumumab, Alemtuzumab, Trastuzumab, Bevacizumab, Ofatumumab, Catumaxomab) sowie ein konjugierter Mab (90Yttrium-Ibritumomab-Tiuxetan) zur Therapie maligner Erkrankungen zugelassen.

Schlüsselwörter

Monoklonale Antikörper Mab Tumor Therapie Immunmodulation 

Monoclonal antibodies in the treatment of malignancy

Abstract

Monoclonal antibodies (mAbs) are industrially produced immunoglobulins that bind to specific protein epitope targets. They play an increasing role as therapeutic agents in the treatment of cancer. MAbs inhibit tumor growth by blocking receptors and manipulating tumor-related signaling or by enhancing the host immune response and targeting factors produced by the tumor. They are also effective in conjugation with radio isotopes or chemotherapy. The adverse effects of mAbs are related to their specific target and to their immunomodulatory properties, which can cause hypersensitivity, immunosuppression, immunostimulation and autoimmunity. In Germany, eight unconjugated (rituximab, cetuximab, panitumumab, alemtuzumab, trastuzumab, bevacizumab, ofatumumab, catumaxomab) and one conjugated (90Yttrium-ibritumomab tiuxetan) mAbs are currently approved for the treatment of malignancies.

Keywords

Monoclonal antibodies MAbs Cancer Therapy Immunomodulation 

Literatur

  1. 1.
    Bang Y, Cutsem E van, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697PubMedCrossRefGoogle Scholar
  2. 2.
    Burkhard M (2006) Monoclonal antibodies. In: Ganten D, Ruckpaul K (Hrsg) Encyclopedic reference of genomics and proteomics in molecular medicine. Springer, Berlin Heidelberg New YorkGoogle Scholar
  3. 3.
    Chen J, Lan K, Hung M (2003) Strategies to target HER2/neu overexpression for cancer therapy. Drug Resist Updat 6:129–136PubMedCrossRefGoogle Scholar
  4. 4.
    Cunningham D, Humblet Y, Siena S et al (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337–345PubMedCrossRefGoogle Scholar
  5. 5.
    Cutsem E van, Köhne C, Hitre E et al (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408–1417PubMedCrossRefGoogle Scholar
  6. 6.
    Descotes J, Gouraud A (2008) Clinical immunotoxicity of therapeutic proteins. Expert Opin Drug Metab Toxicol 4:1537–1549PubMedCrossRefGoogle Scholar
  7. 7.
    Douillard J, Siena S, Cassidy J et al (2010) Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28:4697–4705PubMedCrossRefGoogle Scholar
  8. 8.
    Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8:579–591PubMedCrossRefGoogle Scholar
  9. 9.
    Escudier B, Cosaert J, Pisa P (2008) Bevacizumab: direct anti-VEGF therapy in renal cell carcinoma. Expert Rev Anticancer Ther 8:1545–1557PubMedCrossRefGoogle Scholar
  10. 10.
    Giantonio BJ, Catalano PJ, Meropol NJ et al (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544PubMedCrossRefGoogle Scholar
  11. 11.
    Goldberg RM, Sargent DJ, Thibodeau SN et al (2010) Adjuvant mFOLFOX6 plus or minus cetuximab (Cmab) in patients (pts) with KRAS mutant (m) resected stage III colon cancer (CC): NCCTG Intergroup Phase III Trial N0147. J Clin Oncol 28:3508Google Scholar
  12. 12.
    Hartmann JT, Ulrich J, Kraus S et al (2009) Haut- und Schleimhauttoxizität neuer Substanzen. Onkologe 2:163–168CrossRefGoogle Scholar
  13. 13.
    Hudis CA (2007) Trastuzumab – mechanism of action and use in clinical practice. N Engl J Med 357:39–51PubMedCrossRefGoogle Scholar
  14. 14.
    Kim R (2009) Cetuximab and panitumumab: are they interchangeable? Lancet Oncol 10:1140–1141PubMedCrossRefGoogle Scholar
  15. 15.
    Köhler G, Milstein C (2005) Continuous cultures of fused cells secreting antibody of predefined specificity. 1975. J Immunol 174:2453–2455PubMedGoogle Scholar
  16. 16.
    Leader B, Baca QJ, Golan DE (2008) Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov 7:21–39PubMedCrossRefGoogle Scholar
  17. 17.
    Li S, Schmitz KR, Jeffrey PD et al (2005) Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7:301–311PubMedCrossRefGoogle Scholar
  18. 18.
    Lonberg N (2005) Human antibodies from transgenic animals. Nat Biotechnol 23:1117–1125PubMedCrossRefGoogle Scholar
  19. 19.
    Lundin J, Kimby E, Björkholm M et al (2002) Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 100:768–773PubMedCrossRefGoogle Scholar
  20. 20.
    Maughan TS, Adams R, Smith CG et al (2010) Identification of potentially responsive subsets when cetuximab is added to oxaliplatin-fluoropyrimidine chemotherapy (CT) in first-line advanced colorectal cancer (aCRC): mature results of the MRC COIN trial. J Clin Oncol 28:3502CrossRefGoogle Scholar
  21. 21.
    Miller KD (2003) E2100: a phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer 3:421–422PubMedCrossRefGoogle Scholar
  22. 22.
    Newsome BW, Ernstoff MS (2008) The clinical pharmacology of therapeutic monoclonal antibodies in the treatment of malignancy; have the magic bullets arrived? Br J Clin Pharmacol 66:6–19PubMedCrossRefGoogle Scholar
  23. 23.
    Peeters M, Price TJ, Cervantes A et al (2010) Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28:4706–4713PubMedCrossRefGoogle Scholar
  24. 24.
    Reck M, Pawel J, Zatloukal P von et al (2010) Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 21:1804–1809PubMedCrossRefGoogle Scholar
  25. 25.
    Sandler A, Yi J, Dahlberg S et al (2010) Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer. J Thorac Oncol 5:1416–1423PubMedCrossRefGoogle Scholar
  26. 26.
    Sunada H, Magun BE, Mendelsohn J, MacLeod CL (1986) Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci USA 83:3825–3829PubMedCrossRefGoogle Scholar
  27. 27.
    Suntharalingam G, Perry MR, Ward S et al (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028PubMedCrossRefGoogle Scholar
  28. 28.
    Tabrizi MA, Roskos LK (2007) Preclinical and clinical safety of monoclonal antibodies. Drug Discov Today 12:540–547PubMedCrossRefGoogle Scholar
  29. 29.
    Tveit K, Guren T, Glimelius B et al (2011) Randomized phase III study of 5-fluorouracil/folinate/oxaliplatin given continuously or intermittently with or without cetuximab, as first-line treatment of metastatic colorectal cancer: the NORDIC VII study (NCT00145314), by the Nordic Colorectal Cancer Biomodulation Group. J Clin Oncol 29:365CrossRefGoogle Scholar
  30. 30.
    Verbeek W, Graeven U (2005) Welche Rolle spielen die neuen Therapieoptionen in der palliativen Therapie des Kolonkarzinoms? Internist 46(12):1339–1346PubMedCrossRefGoogle Scholar
  31. 31.
    Vogel CL, Cobleigh MA, Tripathy D et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20:719–726PubMedCrossRefGoogle Scholar
  32. 32.
    Weiner LM, Surana R, Wang S (2010) Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 10:317–327PubMedCrossRefGoogle Scholar
  33. 33.
    Went P, Vasei M, Bubendorf L et al (2006) Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. Br J Cancer 94:128–135PubMedCrossRefGoogle Scholar
  34. 34.
    Zeidler R, Mysliwietz J, Csánady M et al (2000) The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer 83:261–266PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Universitätsmedizin MannheimMannheimDeutschland

Personalised recommendations