Low MSLN shedding enhances efficacy of anticancer agents

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 if shed MSLN enhances or reduces the anti-tumor 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 tumor necrosis factor converting enzyme protease site is replaced with GGGS. We compared the response of the TACE mutant cells to 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 2-3-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 anti-tumor activity of SS1P and RG7787. Approaches that decrease MSLN shedding could enhance the efficacy of immunotoxins and immuno-conjugates targeting MSLN-expressing tumors.

from Cancer via ola Kala on Inoreader http://ift.tt/1OMl4GC
via IFTTT