Blocking sCLU to inhibit EMT in cancer cells
sCLU is a heterodimeric disulphide-linked glycoprotein of 449 amino acids, the over-expression of which has been observed in several malignancies including, prostate, bladder, kidney, breast, colon, and lung tumors. Although the normal biological function of sCLU is unclear, the over-expression of sCLU in cancer cells is often associated with resistance to apoptosis which might contribute to the inherent chemo-resistance of cancer cells undergoing EMT. Several high-affinity mAbs were generated that interact with sCLU and strikingly, when the mAbs were tested in cell-based assays for their ability to block the EMT, the mAbs that neutralized EMT all bound to the same epitope in the sCLU protein. This important discovery demonstrated that a specific region of sCLU was responsible for mediating its EMT-promoting activity. Moreover, the mAbs that blocked the EMT-epitope in sCLU decreased the motility of cells, the expression of mesenchymal markers, and the invasiveness of the cells.
AB-16B5, a novel mAb for the treatment of metastatic cancer
The lead mAb product, AB-16B5, is currently in pre-clinical development in several animal models of metastatic cancer for which treatment options are limited, including invasive breast cancer, hormone-resistant prostate cancer, and pancreatic cancer. So far, these studies revealed that treatment of tumor-harboring mice with AB-16B5 reduced the growth of tumors in combination with chemotherapy. These findings are in complete agreement with the predicted role of sCLU as a potent inducer of chemo-resistance in tumor cells. Additionally, AB-16B5 effectively reduced the spread of tumors cells to secondary organs such as the lungs and the bones, confirming the ability of this anti-sCLU mAb to inhibit EMT in vivo. Taken together, these exciting results completely validate the therapeutic strategy of targeting sCLU to enhance chemo-sensitivity and reduce tumor invasion.
A stable, high-producing CHO cell line was developed which produces the humanized AB-16B5 for GMP manufacturing to carry out toxicology studies in preparation for the filing of an IND soon after.
