Specifically targeted killing of interleukin-13 (IL-13) receptor-expressing breast cancer by IL-13 fusion cytotoxin in animal model of human disease.
Interleukin-13 receptor (IL-13R) alpha2 chain binds IL-13 with high affinity and can internalize after binding to ligand. We have exploited this property of IL-13Ralpha2 chain by receptor-targeted breast cancer therapy. Previous studies have demonstrated that in vivo intratumoral (i.t.) gene transfer of this chain followed by IL-13 cytotoxin [comprised of IL-13 and Pseudomonas exotoxin (IL13-PE38QQR)] therapy causes regression of established human tumors in xenografted models. Breast carcinoma cells do not express IL-13Ralpha2 chain and are resistant to the antitumor effect of IL-13 cytotoxin. To determine whether IL-13Ralpha2 chain can render sensitivity of breast cancer to IL-13 cytotoxin, we injected IL-13Ralpha2 plasmid in s.c. established tumors by i.t. route, followed by systemic or i.t. IL-13 cytotoxin administration. This combination approach showed profound antitumor activity against human breast tumors in xenografted immunodeficient mice. Interestingly, there was dominant infiltration of inflammatory cells in regressing tumors, which were identified to be macrophages producing nitric oxide (NO) and natural killer cells. The partial role of inducible nitric oxide synthase (iNOS)-positive macrophages was confirmed by in vivo macrophage depletion experiments. Serum chemistry, hematology, and organ histology from treated mice did not show any remarkable toxicity resulting from the combination therapy. Taken together, local gene transfer of IL-13Ralpha2 followed by receptor-targeted IL-13 cytotoxin therapy may be applied safely and effectively to the treatment of localized breast cancer.
Kawakami
Koji
K
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
Kawakami
Mariko
M
Puri
Raj K
RK
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005098:Exotoxins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D018793:Interleukin-13 / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D053661:Interleukin-13 Receptor alpha1 Subunit; D015847:Interleukin-4 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010957:Plasmids / Q000235:genetics; D014176:Protein Biosynthesis; D011549:Pseudomonas / Q000737:chemistry; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D013379:Substrate Specificity; D019076:Transgenes / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D005098:Exotoxins; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4