Activity of a recombinant transforming growth factor-alpha-Pseudomonas exotoxin hybrid protein against primary human...

Transforming growth factor-alpha-Pseudomonas exotoxin-40 (TP40) is a recombinant fusion protein. TP40 consists of the entire human transforming growth factor-alpha (TGF alpha) protein fused to a 40,000 Da. segment of the Pseudomonas exotoxin A protein. TP40 is a bifunctional molecule that possesses the epidermal growth factor (EGF) receptor binding properties of TGF alpha and the cell killing properties of Pseudomonas exotoxin A. These properties make TP40 a selective cytotoxic agent that kills EGF receptor bearing cells. TP40 has been shown to effectively kill human tumor cell lines that possess EGF receptors in vitro and in nude mice. In the present study, TP40 was tested against tumors taken directly from patients and grown in a soft agar human tumor cloning system. A total of 107 patients' tumors (taken from patients with tumors refractory to chemotherapy) were tested with a continuous exposure to 0.5-50 nM concentrations of the agent. TP40 exhibited a clear dose response effect against a wide variety of human solid tumor colony-forming units with greater than or equal to 84% of evaluable tumors responding at a drug concentration greater than or equal to 24 nM. When used as a continuous exposure, concentrations of TP40 as low as 5 nM demonstrated substantial in vitro activity. This activity included cytotoxicity against breast, colorectal, endometrial, head and neck, non small-cell lung, gastric, sarcoma, and pancreatic cancer tumor colony-forming units. Additional in vivo testing of this compound is warranted.