Receptor for interleukin 13 on AIDS-associated Kaposi's sarcoma cells serves as a new target for a potent Pseudomonas exotoxin-based chimeric toxin protein.
AIDS-associated Kaposi's sarcoma (AIDS-KS), the most common malignant complication of human immunodeficiency virus infection, is characterized by neoplastic proliferation of mesenchymal cells. AIDS-KS cells release and respond to an array of cytokines through specific plasma membrane receptors. Specific targeting of potent cytotoxic agents to cell surface receptors/antigens on Kaposi's sarcoma cells may provide effective therapy for this malignancy. We have identified a new target in the form of an interleukin 13 (IL-13) receptor that is overexpressed in the five AIDS-KS cell lines examined. Radiolabeled IL-13 cross-linked to a single protein of about Mr 70,000 in AIDS-KS cells. We utilized a chimeric cytotoxic protein composed of IL-13 and a truncated Pseudomonas exotoxin (IL13-PE38QQR), which was found to be specifically and highly cytotoxic to AIDS-KS cells, as determined by protein synthesis inhibition and clonogenic assays. IL13-PE38QQR demonstrated significant antitumor activity in a human epidermoid carcinoma xenograft model. Normal human umbilical vein-derived endothelial, lymphoid, and bone marrow precursor cells expressed low levels of IL-13 receptors, and IL-13 toxin was not cytotoxic to them. Thus, IL-13 receptor on AIDS-KS cells may represent a novel plasma membrane protein(s) that could be utilized to target therapeutic agents.
Husain
S R
SR
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Obiri
N I
NI
Gill
P
P
Zheng
T
T
Pastan
I
I
Debinski
W
W
Puri
R K
RK
D036002:ADP Ribose Transferases; D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001427:Bacterial Toxins; D005098:Exotoxins / Q000494:pharmacology*; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D018793:Interleukin-13 / Q000378:metabolism* / Q000494:pharmacology; D053661:Interleukin-13 Receptor alpha1 Subunit; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000187:drug effects; D053660:Receptors, Interleukin-13; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D011500:Protein Synthesis Inhibitors; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508181:IL13RA1 protein, human