EXTH-23. QUAD-DM1: A highly potent drug conjugate for treatment of breast cancer brain metastasis

Abstract Brain metastatic cancers remain an unmet need in medicine. For patients with metastatic breast cancer to the brain, treatment is limited and largely ineffective. Previously, we and others have found 4 receptors that collectively are over-expressed in nearly all patients with glioblastoma (GBM): EphA2, EphA3, EphB2, and interleukin 13 receptor alpha 2 (IL-13RA2). We developed an innovative multivalent therapeutic, termed QUAD-DM1, which targets all four of these receptors and is conjugated with a microtubule-disrupting agent. This compound demonstrates a specific potency killing on GBM cells, in nanomolar range. While examining the presence of these four targeted receptors in breast cancer cells with tissue-micro arrays and paired primary tumor and brain metastases, we found that the four targeted receptors are over-expressed in almost all breast cancer and related metastases to the brain. With this knowledge, we then studied a triple negative breast cancer (TNBC) brain metastatic cell line, MDA-MB-231-BrM cells, and found it to be highly responsive to our QUAD cytotoxin, with an IC50 <10-11M. Cell killing was blocked with QUAD alone, without DM1, indicating specificity and confirming the killing was receptor dependent. Derived from the MDA-MB-231 parental cell line, MDA-MB-231-BrM cells maintain over-expression of our 3 targeted Eph receptors and gain IL-13RA2 protein expression when analyzed by western blot. All four receptors were also detected on the cell surface by flow cytometry. Additionally, we compared QUAD-DM1 treatment to the current standard of care like Trastuzumab-emtansine (T-DM1). When MDA-MB-231-BrM cells were implanted intracranially in athymic mice, there was a significant response to a single intracranial bolus, non-dose-optimized injection of 4.0 µg QUAD-DM1 without toxicity. QUAD-DM1 is a powerful novel multivalent drug conjugate for the treatment of metastatic breast cancer to the brain and may be particularly well suited to treat TNBC patients, where there are few viable options.