EXTH-10. QUAD-DM1: A HIGHLY POTENT DRUG CONJUGATE FOR BREAST CANCER AND BREAST CANCER BRAIN METASTASIS TREATMENT

Abstract

Abstract Triple-negative breast cancer (TNBC) remains an unmet need in medicine. Previously, we and others found that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed in almost all patients with glioblastoma (GBM). We performed a first-of-a-kind Phase I clinical trial in dogs with spontaneous gliomas using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. The majority of dogs experienced >50% of tumor regression; four dogs exhibited >92% tumor shrinkage and several dogs became long-term survivors. Next, we pursued the novel idea of targeting four tumor-associated receptors, instead of two, with one pharmaceutical compound. To this end, we produced a multivalent ligand, termed QUAD. More recently, we found that a conjugate of QUAD with emtansine (DM1), a microtubule-disrupting agent, demonstrated a specific killing potency on GBM cells, in low picomolar range. Unexpectedly, we observed that human breast cancer cells are also highly responsive to this drug candidate. We thus examined the presence of the four receptors in breast cancer cells and tissue micro-arrays, including involved lymph nodes, and in paired primary tumor - brain metastases, spanning two molecular subtypes of breast cancer: TNBC and HER2+. We found that the four targeted receptors are expressed in almost all breast cancer and related metastases to brain specimens, based on the expression levels for the genes and the gene products. Furthermore, the breast cancer cell lines like HC1806, MDA-MB-468, MDA-MB-231, BT549, and the breast metastatic cell line MDA-MB-231-BRM cells are killed at up to picomolar concentrations of QUAD-DM1. MDA-MB-231 tumors growing in mammary pads of athymic mice responded significantly to QUAD-DM1 given intravenously; QUAD recognizes murine receptors similarly to human. Thus, QUAD-DM1 is a novel type of a multivalent drug conjugate for the treatment of breast cancer and its brain metastases, which is applicable, but not exclusively, to TNBC.