Interleukin 4-Toxin in Mice with Interleukin 4 Receptor-bearing Increased Antitumor Activity of a Circularly Permuted

نویسندگان

  • Robert J. Kreitman
  • Raj K. Puri
  • Ira Pastan
چکیده

We reported previously that circularly permuted interIeukin-4 (IL4), composed of amino acids 38-129 of IL4 connected by a linker peptide GGNGG to amino acids 1-37, is preferable to native II ,4 for fusing to the amino terminus of truncated Pseudomonas exotoxin (PE) to make a recombinant toxin, because the new ligand-toxin junction results in im proved IL4 receptor (IL4R)-binding (R. J. Kreitman et al, Proc. Nati. Acad. Sci. USA, 91: 6889-6893, 1994). We now report that the improved binding of circularly permuted IL4-toxin is associated with improved antitumor activity in tumor-bearing mice. For in vivo testing, we made an improved circularly permuted IL4-toxin, termed IL4(38-37)-PE38KDEL. It contains an N38D mutation at the amino terminus, allowing improved expression and large-scale production in Escherìchìa coli. It also contains the truncated toxin PE38KDEL, which is composed of amino acids 253364 and 381-608 of PE, followed by KDEL. To evaluate antitumor activity, nude mice carrying s.c. tumors composed of IL4R-bearing human A431 epidermoid carcinoma cells were injected with recombinant toxins i.v. every other day for three doses. IL4(38-37)-PE38KDEL induced com plete remissions in 80% of mice receiving 50 ug/kg x 3 and 100% of mice receiving 100 ug/kg x 3, while only 70% of mice receiving 200 ug/kg x 3 of the native IL4-toxin IL4-PE38KDEL obtained complete remission. Disease-free survival after obtaining complete remissions was higher in mice treated with IL4(38-37)-PE38KDEL 50 ug/Kg QOD x 3 than with IL4-PE38KDEL 200 ug/Kg QOD x 3 (P < 0.03). IL4(38-37)-PE38KDEL and IL4-PE38KDEL exhibited similar toxicity and pharmacokinetics in the mice, indicating that the improved antitumor activity of the circularly permuted IL4-toxin was due to its improved binding to the IL4R on the

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تاریخ انتشار 2006