Immunotoxins

Details Immunotoxins Immunotoxins

A - Human Necessities

61

K

A61K 39/395 (2006.01) A61K 35/74 (2006.01) A61K 47/48 (2006.01) A61P 35/00 (2006.01) C07K 14/705 (2006.01) C07K 16/28 (2006.01) C07K 16/30 (2006.01) C07K 19/00 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2424255

Ep-CAM is a tumor-associated antigen overexpressed in many solid tumors but shows limited expression in normal epithelial tissues. To exploit this favorable expression pattern for targeted cancer therapy an Ep-CAM-specific recombinant immunotoxin was developed and its antitumor activity investigated. The immunotoxin 4D5MOCB-ETA was developed by genetically fusing a truncated form of ETA (ETA252-608KDEL) to the highly stable humanized scFv 4D5MOCB. Cytotoxicity of 4D5MOCB-ETA was measured in cell growth and leucine incorporation assays in vitro Tumor localization and antitumor activity were assessed in athymic mice bearing established human tumor xenografts. Fusion of the toxin moiety to the scFv did neither affect its thermal stability nor its antigen binding affinity. In vitro, 4D5MOCB-ETA potently and specifically inhibited protein synthesis and reduced the viability of Ep-CAM- positive carcinoma cells of diverse histological origins with IC50 values ranging from 0.005 to 0.2 pM. Upon systemic administration in mice,4D5MOCB-ETA showed similar organ distribution as the scFv 4D5MOCB and preferentially localized to Ep-CAM-positive tumor xenografts with a tumorblood ratio of 5.4. The potent antitumor activity of 4D5MOCB-ETA was demonstrated by its ability to strongly inhibit the growth and induce regression of relatively large tumor xenografts derived from lung, colon or squamous cell carcinomas

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