Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-19529
Bauer, S; Oosterwijk-Wakka, J C; Adrian, N; Oosterwijk, E; Fischer, E; Wüest, T; Stenner, F; Perani, A; Cohen, L S; Knuth, A; Divgi, C; Jäger, D; Scott, A M; Ritter, G; Old, L J; Renner, C (2009). Targeted therapy of renal cell carcinoma: synergistic activity of cG250-TNF and IFNg. International Journal of Cancer, 125(1):115-123.
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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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology|
|DDC:||610 Medicine & health|
|Date:||01 July 2009|
|Deposited On:||03 Jul 2009 14:13|
|Last Modified:||12 Apr 2012 05:30|
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