Targeted therapy of renal cell carcinoma: Synergistic activity of cG250-TNF and IFNg Journal Article

Authors: Bauer, S.; Oosterwijk-Wakka, J. C.; Adrian, N.; Oosterwijk, E.; Fischer, E.; Wüest, T.; Stenner, F.; Perani, A.; Cohen, L.; Knuth, A.; Divgi, C.; Jäger, D.; Scott, A. M.; Ritter, G.; Old, L. J.; Renner, C.
Article Title: Targeted therapy of renal cell carcinoma: Synergistic activity of cG250-TNF and IFNg
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-c (IFNγ). Biodistribution data on radiolabeled [<sup>125</sup>J] cG250-TNF and antitumor activity of cG250-TNF, alone and in combination with IFNγ, were measured on RCC xenografts in BALB/c nu/nu mice. Combined administration of cG250-TNF and IFNγ 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 IFNγ without significant increase in side effects. Administration of cG250-TNF and IFNγ 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. © 2009 UICC.
Keywords: controlled study; protein expression; human cell; overall survival; drug activity; drug potentiation; monotherapy; nonhuman; flow cytometry; chemical analysis; animal cell; mouse; animal; cytology; metabolism; animals; mice; animal tissue; cells, cultured; cancer immunotherapy; low drug dose; progression free survival; animal experiment; animal model; antineoplastic activity; in vitro study; drug effect; drug screening; pathology; xenograft model antitumor assays; tumor antigen; mice, inbred balb c; kidney carcinoma; kidney neoplasms; monoclonal antibody; drug dose escalation; drug synergism; cancer inhibition; immunology; cytokines; antibodies, monoclonal; hybrid protein; tumor necrosis factor alpha; bagg albino mouse; mononuclear cell; antigens, neoplasm; leukocytes, mononuclear; recombinant fusion proteins; tumor necrosis factor-alpha; recombinant antibody; renal cell cancer; tumor targeting; carbonate dehydratase ix; gamma interferon; immunoglobulin g; iodine 125; iodine 131; recombinant tumor necrosis factor; cancer vaccine; diagnostic agent; monoclonal antibody g250; radioactive iodine; recombinant gamma interferon; biological activity; drug accumulation; drug distribution; drug mechanism; drug retention; drug uptake; genetic engineering; isotope labeling; xenograft; cell culture; drug combination; kidney tumor; nude mouse; tissue distribution; umbilical vein; vascular endothelium; cancer vaccines; carcinoma, renal cell; drug therapy, combination; endothelium, vascular; interferon-gamma, recombinant; iodine radioisotopes; mice, nude; umbilical veins
Journal Title: International Journal of Cancer
Volume: 125
Issue: 1
ISSN: 0020-7136
Publisher: John Wiley & Sons  
Date Published: 2009-07-01
Start Page: 115
End Page: 123
Language: English
DOI: 10.1002/ijc.24359
PUBMED: 19384924
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 5" - "Export Date: 30 November 2010" - "CODEN: IJCNA" - "Source: Scopus"
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MSK Authors
  1. Leonard Cohen
    18 Cohen
  2. Gerd Ritter
    158 Ritter
  3. Lloyd J Old
    385 Old