Targeted therapy of renal cell carcinoma: synergistic activity of cG250-TNF and IFNg.
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.
Bauer
Stefan
S
Oncology Department, Universitäts Spital Zürich, Zürich, Switzerland. stefan1.bauer@med.uni-heidelberg.de
Oosterwijk-Wakka
Jeannette C
JC
Adrian
Nicole
N
Oosterwijk
Egbert
E
Fischer
Eliane
E
Wüest
Thomas
T
Stenner
Frank
F
Perani
Angelo
A
Cohen
Leonard
L
Knuth
Alexander
A
Divgi
Chaitanya
C
Jäger
Dirk
D
Scott
Andrew M
AM
Ritter
Gerd
G
Old
Lloyd J
LJ
Renner
Christoph
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000493:pharmacokinetics / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D007371:Interferon-gamma / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C106533:G250 monoclonal antibody; D007074:Immunoglobulin G; D007457:Iodine Radioisotopes; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma