DDEL-14. NOVEL BLOOD BRAIN BARRIER PENETRATING BI-SPECIFIC ANTIBODY THERAPY FOR BREAST CANCER BRAIN METASTASIS

Abstract Breast cancer is the second leading cause for brain metastasis after lung cancer. While Her2 +ve tumors respond to her2 targeted antibody therapy, these antibodies are unable to cross the blood brain tumor barrier to effectively target metastases hidden in the ‘CNS sanctuary’. To overcome this hurdle, we have modified Her2 targeting Herceptin to create a CNS penetrating antibody that is transported in a unidirectional fashion into brain tumors. The modified BBB penetrating Herceptin is processed by the tumor specific microenvironment after crossing the BBB, such that the modified antibody is then trapped in the tumor ECM. This has the potential to increase tumor retention and reduce systemic toxicity. The BBB penetrant anti Her2 antibody (Herceptin) binds to Her2 on breast cancer cells and suppresses activation of Her2 signaling in vitro. Western blot analysis shows reduction of Her2 phosphorylation and down stream signaling with both unmodified and BBB modified Herceptin. This permits recruitment and retention of the antibody into the CNS tumors. Using fluorescence imaging and IHC of intracranial tumors we have validated that the BBB modified Herceptin is localized into intracranial tumors. We are currently evaluating the safety and therapeutic benefit of this approach in mice bearing intracranial tumors.