gms | German Medical Science

27. Deutscher Krebskongress

Deutsche Krebsgesellschaft e. V.

22. - 26.03.2006, Berlin

Growth Inhibition of Solid Tumors by Intravenous Application of cG250-TNF

Meeting Abstract

  • corresponding author presenting/speaker Stefan Bauer - Oncology Dept. Universitätsspital Zürich, Schweiz
  • Egbert Oosterwijk - Urology Dept., Nijmegen, Netherlands
  • Frank Stenner - Oncology Dept. Universitätsspital Zürich, Schweiz
  • Sascha Kleber - Oncology Dept. Universitätsspital Zürich, Schweiz
  • Michael Pfreundschuh - Med. Department I, Universität des Saarlandes, Homburg
  • Andrew Scott - Ludwig Institute for Cancer Research, Austin and Repatriation Medical Center, Heidelberg, Victoria, Australia
  • Gerd Ritter - Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, NY, NY, USA
  • Lloyd Old - Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, NY, NY, USA
  • Christoph Renner - Oncology Dept. Universitätsspital Zürich, Schweiz

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocOP437

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter:

Veröffentlicht: 20. März 2006

© 2006 Bauer et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen ( Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.



Introduction: Cell surface appearance of G250 is induced upon malignant transformation and has been identified in a number of solid tumors, including renal carcinoma, esophageal and colorectal carcinoma, bladder carcinoma and non-small cell lung carcinoma. Normal tissue expression is limited to larger bile duct epithelium and stomach mucosal cells. The safe administration of the radiolabeled chimeric anti-G250 antibody (131I cG250) was demonstrated in a phase I clinical trial on patients with metastatic clear cell renal cancer. Unfortunately, fractionated radioimmunotherapy did not result in any major clinical responses despite excellent tumor targeting. An ongoing phase I / II clinical trial on patients with advanced renal cell carcinomas reports a better outcome after combined treatment with uncoupled cG250 antibody and IL-2 when compared to historical controls.

Methods: We genetically engineered a cG250-TNF fusion protein. Eucariontic expression was optimized under serum-free conditions. Biochemical characterization and bioactivity analysis were performed in-vitro using gel filtration chromatography, optical biosensor measurements and cytotoxicity assays. Biodistribution data on radiolabeled 125J G250-TNF and antitumor activity of G250-TNF were measured on G250-expressing xenografts in BALB/c nu/nu mice.

Results: To improve effectiveness of the unbound antibody, we displayed a new TNF-immunocytokine with the variable heavy- and light chain regions of cG250. In analogy to our previously described fusion proteins, human TNF monomers replace the IgG1 CH2/CH3 Fc domain. In contrast to trimerized wild type TNF, this construct preserved its IgG1-derived dimeric structure with the TNF molecule forced to form a dimer. Leaving the 3-fold symmetry of TNF resulted in an optimized structure-activity relationship with excellent tumor targeting properties and manifold reduction of unwanted systemic toxicity when compared to wild type TNF or uncoupled parental cG250. The favourable toxicity-profile allowed for application of increased immunocytokine doses resulting in significant antitumor activity in-vivo.