The antimelanoma immunocytokine scFvMEL/TNF shows reduced toxicity and potent antitumor activity against human tumor xenografts.
The immunocytokine scFvMEL/TNF, a fusion protein composed of human tumor necrosis factor (TNF) and a single-chain Fv antibody (scFv) scFvMEL targeting the melanoma gp240 antigen, demonstrates impressive cytotoxic effects against human melanoma cell lines in vitro. Pharmacokinetic studies of 125I-scFvMEL/TNF in BALB/c mice showed that the construct clears from the circulation with a terminal-phase half-life of 17.6 hours after intravenous administration. The maximum tolerated dose of scFvMEL/TNF in nude mice was 4 mg/kg, i.v., on a daily x5 schedule. There were no changes in gross pathology, clinical chemistry, or hematologic parameters in mice treated at doses of up to 3 mg/kg. Therapeutic studies at a dose of 2.5 mg/kg on athymic mice bearing established (approximately 50 mm3) human melanoma A375GFP xenograft tumors transfected with green fluorescent protein demonstrated potent tumor suppression and complete tumor regression of all lesions. There was no subsequent outgrowth of tumors from mice rendered tumor-free. These data show that scFvMEL/TNF can target melanoma cells in vivo and can result in pronounced antimelanoma effects after systemic administration. Toxicology studies indicate the relative safety of this agent at doses that are therapeutically effective and provide guidance to projected phase I starting doses on patients at this schedule.
Liu
Yuying
Y
Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Zhang
Weihe
W
Cheung
Lawrence H
LH
Niu
Ting
T
Wu
Qingping
Q
Li
Chun
C
Van Pelt
Carolyn S
CS
Rosenblum
Michael G
MG
D000818:Animals; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000922:Immunotoxins / Q000737:chemistry; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology; D057127:Single-Chain Antibodies; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000922:Immunotoxins; D007457:Iodine Radioisotopes; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D014409:Tumor Necrosis Factor-alpha; C512973:scFvMEL-TNF fusion protein; D049452:Green Fluorescent Proteins