Advertisement

Nach dem TGN1412-Zwischenfall

Prinzipien der Bewertung von First-in-Man-Studien mit monoklonalen Antikörpern durch das Paul-Ehrlich-Institut
  • C. K. Schneider
  • U. Kalinke
Leitthema: Originalien und Übersichtsarbeiten

Zusammenfassung

Der Einsatz monoklonaler Antikörper hat auf vielen klinischen Gebieten zu neuen therapeutischen Möglichkeiten geführt. Er birgt aber auch Risiken, wie das akute Auftreten eines Zytokinsturms bei der Erstanwendung von TGN1412, einem Superagonisten gegen CD28, im März 2006 gezeigt hat. Dieser Artikel beschreibt die Prinzipien, die das Paul-Ehrlich-Institut (PEI) bei der wissenschaftlichen Bewertung von Anträgen auf klinische Prüfung zur Erstanwendung von monoklonalen Antikörpern am Menschen anwendet. Diese werden als Verfahrensanweisung in das Qualitätsmanagementsystem des PEI implementiert und stellen eine Ergänzung und Konkretisierung der allgemeinen Leitlinie des Ausschusses für Humanarzneimittel (CHMP) für die Produktklasse der monoklonalen Antikörper dar. Wesentliche Aspekte sind die auf monoklonale Antikörper zugeschnittenen Faktoren zur Abschätzung des Risikos, da nicht jeder monoklonaler Antikörper per se ein Risiko darstellt, sowie die Gründung einer PEI-Expertengruppe, die die wissenschaftliche Bewertung begleitet und prüft.

Schlüsselwörter

TGN1412 Risikobewertung Monoklonale Antikörper Klinische Prüfung First-in-Man-Studie 

After the TGN1412 incident. Principles for assessment of first-in-man trials with monoclonal antibodies by the Paul Ehrlich Institute

Abstract

The use of monoclonal antibodies has led to new therapeutic possibilities for many clinical conditions. However, their application also bears risks, as demonstrated by the acute occurrence of a cytokine storm following administration of TGN1412, an anti-CD28 superagonist, in March 2006. This article highlights the principles of the Paul-Ehrlich-Institut (PEI) for the scientific assessment of first-in-man clinical trial applications for monoclonal antibodies. These principles are implemented as a standard operating procedure in the PEI Quality Management System and are intended as a supplement specific to monoclonal antibodies to the published general guideline issued by the Committee for Medicinal Products for Human Use (CHMP). Central aspects are the identification of risk factors for monoclonal antibodies based on defined criteria, since not every novel monoclonal antibody represents a risk per se. Furthermore, a PEI expert group that supports the scientific assessment procedure has been founded.

Keywords

TGN1412 risk evaluation monoclonal antibodies clinical trial first-in-man trial 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    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(10):1018–1028PubMedCrossRefGoogle Scholar
  2. 2.
    Luhder F, Huang Y, Dennehy KM, et al. (2003) Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J Exp Med 197(8):955–966PubMedCrossRefGoogle Scholar
  3. 3.
    Bour-Jordan H, Bluestone J (2002) CD28 function: a balance of costimulatory and regulatory signals. J Clin Immunol 22(1):1–7PubMedCrossRefGoogle Scholar
  4. 4.
    Beyersdorf N, Gaupp S, Balbach K, et al. (2005) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202(3):445–455PubMedCrossRefGoogle Scholar
  5. 5.
    Hohlfeld R, Wekerle H (2004) Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci USA 101(Suppl 2):14599–14606PubMedCrossRefGoogle Scholar
  6. 6.
    Skapenko A, Lipsky PE, Schulze-Koops H (2006) T cell activation as starter and motor of rheumatic inflammation. Curr Top Microbiol Immunol 305:195–211PubMedCrossRefGoogle Scholar
  7. 7.
    Winkler U, Jensen M, Manzke O, et al. (1999) Cytokine-release syndrome in patients with Bcell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 94(7):2217–2224PubMedGoogle Scholar
  8. 8.
    Hopkin M (2006) Can super-antibody drugs be tamed? Nature 13; 440(7086):855–856Google Scholar
  9. 9.
    Expert Scientific Group on Phase One Clinical Trials: Final Report (The Stationary Office, Norwich, United Kingdom, 2006) ISBN-10 0 11 703722 2. http://www.dh.gov.uk/en/Consultations/Closedconsultations/DH_4139038Google Scholar
  10. 10.
    Agence Française de Sécurité Sanitaire des Produits de Santé (AFSSAPS) Department for the Evaluation of Special Status Medicinal Products, First-in-man clinical trials: Estimation of the starting dose, definition of dose progression and protocol of administration to volunteers, 25 July 2006, reviewed 5 September 2006, http://www.afssaps.sante.frGoogle Scholar
  11. 11.
    Medicines and Healthcare products Regulatory Agency (MHRA) First-in-man trials with monoclonal antibodies or other high risk compounds, Standard questions for studies covered by the interim arrangements (2006), http://www.mhra.gov.ukGoogle Scholar
  12. 12.
    Schneider CK, Kalinke U, Löwer, J (2006) TGN1412 – a regulator's perspective. Nat Biotechnol 24(5):493–496PubMedCrossRefGoogle Scholar
  13. 13.
    European Medicines Agency (EMEA) (2007) Guideline on Requirements for First-in-Man Clinical Trials for Potential High-Risk Medicinal Products EMEA/CHMP/SWP/28367/2007. http://www.emea.europa.eu/pdfs/human/swp/2836707en.pdfGoogle Scholar
  14. 14.
    European Medicines Agency (EMEA) (1998) ICH Topic S6. Note for Guidance on Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals CPMP/ICH/302/95. http://www.emea.europa.eu/pdfs/human/ich/030295en.pdfGoogle Scholar
  15. 15.
    Hanke T (2006) Lessons from TGN1412. Lancet 368(9547):1569–1570PubMedCrossRefGoogle Scholar
  16. 16.
    Presta LG, Namenuk AK (2005) Non-human primate Fc receptors and methods of use. In USPTO patent full-text and image database San Francisco: GenentechGoogle Scholar
  17. 17.
    Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7(2):118–130PubMedCrossRefGoogle Scholar
  18. 18.
    U.S. Food and Drug Administration (FDA) (2002) Guidance for industry and reviewers: estimating the safe starting dose in clinical trials for therapeutics in adult healthy Volunteers. http://www.fda.gov/CbER/gdlns/dose.pdfGoogle Scholar
  19. 19.
    Schäffner G (2007) Using the correct terminology. Reg Affairs J 18(1):3–5Google Scholar
  20. 20.
    European Medicines Agency (EMEA) (2006) European public assessment Report for Xolair. http://www.emea.europa.eu/humandocs/Humans/EPAR/xolair/xolair.htmGoogle Scholar
  21. 21.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (1997) ICH Guideline E8: General Considerations for Clinical Trials. http://www.ich.org/LOB/media/MEDIA484.pdfGoogle Scholar

Copyright information

© Springer Medizin Verlag 2007

Authors and Affiliations

  1. 1.Paul-Ehrlich-InstitutLangenBRD
  2. 2.Paul-Ehrlich-InstitutLangenBRD

Personalised recommendations