Targeting of tumor cells and tumor stem cells by antibodies specific for the cell-bound alpha/beta junction of MUC1.

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e13018 Background: MUC1 is a glycoprotein over-expressed on the cell surface of a variety of malignancies and has long been a subject of interest in targeted therapy.Cleavage of MUC1 yields two unequal chains, a large extracellular a subunit non-covalently bound to a smaller b subunit in an on-and-off mechanism. Because it is released into the peripheral circulation, the MUC1 a subunit readily sequesters antibodies directed against it. In order to avoid such peripheral sequestration, Abs directed against MUC1 must be engineered as to target cell bound moieties of MUC1. Methods: Seven anti-MUC1 monoclonal antibodies were generated, five Ig-gamma1 and two IgA, all directed against the MUC1 a/b junction, a structure which remains cell bound at all times. Results: In addition to their binding differentiated breast cancer cells at pico Molar concentrations, the anti-MUC1 mAbs strongly bind breast cancer stem cells. With a view for clinical application, the DMB5F3 anti-MUC1 mAb was partially humanized with resultant production of chimeric IgG1. In order to demonstrate that chimeric anti-MUC1 antibodies can be used in tumor cell killing, mAb DMB5F3 was linked to the pseudomonas bacterial exotoxin ZZ-PE38. The resultant anti-MUC1 immunotoxin not only efficiently internalized the toxin, it resulted in strong cytotoxicity of MUC1+ breast cancer. In fact, DMB5F3:PE38 immunotoxin bound MUC1+ cancer cells with an affinity (Ab concentrations as low as 20pM) exceeding that seen with cetuximab (anti-EGFR1)-PE38 and tratuzumab (anti-erbB2)-PE38 immunotoxins. Conclusions: Taken together, these findings indicate [1] the therapeutic use of targeting cell-bound MUC1 [2] high affinity activity against both tumor and tumor stem cells suggests that the anti-MUC1 mAbs target not only 'mature' differentiated malignancy but self-reproducing cells giving rise to new malignant growth as well [3]tumor can be targeted directly by anti-MUC1 antibodies or by linking anti-MUC1 to toxin, resulting in efficient immunotoxin cytotoxicity [4] as it was shown to be a targetable entity, the SEA domain represents a promising immunogen for MUC1 tumor vaccines.