Targeted therapy of renal cell carcinoma: Synergistic activity of cG250-TNF and IFNg Academic Article uri icon

abstract

  • Immunotherapeutic targeting of G250/Carbonic anhydrase IX (CA-IX) represents a promising strategy for treatment of renal cell carcinoma (RCC). The well characterized human-mouse chimeric G250 (cG250) antibody has been shown in human studies to specifically enrich in CA-IX positive tumors and was chosen as a carrier for site specific delivery of TNF in form of our IgG-TNF-fusion protein (cG250-TNF) to RCC xenografts. Genetically engineered TNF constructs were designed as CH2/CH3 truncated cG250-TNF fusion proteins and eucariotic expression was optimized under serum-free conditions. In-vitro characterization of cG250-TNF comprised biochemical analysis and bioactivity assays, alone and in combination with Interferon-gamma (IFNgamma). Biodistribution data on radiolabeled [(125)J] cG250-TNF and antitumor activity of cG250-TNF, alone and in combination with IFNgamma, were measured on RCC xenografts in BALB/c nu/nu mice. Combined administration of cG250-TNF and IFNgamma caused synergistic biological effects that represent key mechanisms displaying antitumor responses. Biodistribution studies demonstrated specific accumulation and retention of cG250-TNF at CA-IX-positive RCC resulting in growth inhibition of RCC and improved progression free survival and overall survival. Antitumor activity induced by targeted TNF-based constructs could be enhanced by coadministration of low doses of nontargeted IFNgamma without significant increase in side effects. Administration of cG250-TNF and IFNgamma resulted in significant synergistic tumoricidal activity. Considering the poor outcome of renal cancer patients with advanced disease, cG250-TNF-based immunotherapeutic approaches warrant clinical evaluation.

authors

  • Bauer, Stefan
  • Oosterwijk-Wakka, Jeannette C
  • Adrian, Nicole
  • Oosterwijk, Egbert
  • Fischer, Eliane
  • Wüest, Thomas
  • Stenner, Frank
  • Perani, Angelo
  • Cohen, Leonard
  • Knuth, Alexander
  • Divgi, Chaitanya
  • Jäger, Dirk
  • Scott, Andrew M
  • Ritter, Gerd
  • Old, Lloyd J
  • Renner, Christoph

publication date

  • July 1, 2009

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