Reduced Shedding of Surface Mesothelin Improves Efficacy of Mesothelin-Targeting Recombinant Immunotoxins
| Autor: | Tapan K. Bera, Prince Awuah, Oleg Chertov, Messan Folivi, Ira Pastan |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Recombinant Fusion Proteins Mutant Gene Expression Antineoplastic Agents GPI-Linked Proteins Article law.invention 03 medical and health sciences 0302 clinical medicine Antigen Immunotoxin law Cell Line Tumor Animals Humans Mesothelin Dose-Response Relationship Drug biology Immunotoxins Cell Membrane Antibodies Monoclonal Xenograft Model Antitumor Assays Molecular biology Disease Models Animal 030104 developmental biology Oncology Drug Resistance Neoplasm Cell culture 030220 oncology & carcinogenesis Mutation Monoclonal Recombinant DNA biology.protein Cancer research Antibody |
| Zdroj: | Molecular Cancer Therapeutics. 15:1648-1655 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Mesothelin (MSLN) is a differentiation antigen that is highly expressed in many epithelial cancers. MSLN is an important therapeutic target due to its high expression in cancers and limited expression in normal human tissues. Although it has been assumed that shed antigen is a barrier to immunotoxin action, a modeling study predicted that shed MSLN may enhance the action of MSLN-targeting recombinant immunotoxins such as SS1P and similar therapeutics by facilitating their redistribution within tumors. We aimed to determine whether shed MSLN enhances or reduces the antitumor effect of MSLN-targeting immunotoxins SS1P and RG7787. We engineered a cell line, A431/G9 (TACE mutant) that expresses a mutant form of MSLN in which the TNF-converting enzyme protease site is replaced with GGGS. We compared the response of the TACE-mutant cells with immunotoxins SS1P and RG7787 with that of the parental A431/H9 cell line. We show that TACE-mutant cells shed 80% less MSLN than A431/H9 cells, that TACE-mutant cells show a 2- to 3-fold increase in MSLN-targeted immunotoxin uptake, and that they are about 5-fold more sensitive to SS1P killing in cell culture. Tumors with reduced shedding respond significantly better to treatment with SS1P and RG7787. Our data show that MSLN shedding is an impediment to the antitumor activity of SS1P and RG7787. Approaches that decrease MSLN shedding could enhance the efficacy of immunotoxins and immunoconjugates targeting MSLN-expressing tumors. Mol Cancer Ther; 15(7); 1648–55. ©2016 AACR. |
| Databáze: | OpenAIRE |
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