High mobility group box-1 (HMGB1), originally identified as a nuclear chromatin DNA-binding protein, plays a very important role in triggering the inflammatory responses in many kids of diseases once released into extracellular space. HMGB1 directly stimulates RAGE and TLR-4/2, and enhances the signal transduction by forming complexes with CXCL12 and IL-1beta. In the previous studies, we demonstrated that the treatment with anti-HMGB1 monoclonal antibody (mAb) produced the beneficial effects on a diverse range of CNS and PNS diseases including brain ischemia, hemorrhage, trauma, epilepsy and neuropathic pain using animal models. During the studies, we noticed that the treatment with anti-HMGB1 mAb protected blood-brain barrier (BBB) from disruption very efficiently. Then, we focused on the distribution of therapeutic mAb in vivo and found that it accumulated around BBB in some types of brain injuries. To further investigate the dynamics of HMGB1 in vascular endothelial cells and the effects of anti-HMGB1 mAb, we used in vitro endothelial cell culture. We found that anti-HMGB1 mAb inhibited the stimulation-induced translocation of HMGB1, associated with the reduction of cytokine production. Surprisingly, anti-HMGB1 mAb was incorporated into endothelial cells considerably and we hypothesized that this incorporation could be applicable to DDS of anti-cancer drugs to tumor vessels. We will present in vivo data on the effects of conjugated mAb on melanoma in mice.