Magic™ Anti-Angiostatin monoclonal antibody, clone F22

Dengue virus (DENV) infection is the most common mosquito-borne viral disease, and it can cause life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Abnormal activation of the coagulation and fibrinolysis system is one of the hallmarks of DHF/ DSS. However, the mechanism underlying hemorrhage in DHF/ DSS remains elusive. In previous studies, plasminogen (Plg) cross-reactive Abs, which can recognize DENV nonstructural protein (NS) 1, have been found in dengue patients. However, it is unclear whether these Abs are indeed induced by DENV NS1. Thus, we immunized mice with recombinant NS1 from both bacteria and drosophila to determine whether NS1 can induce Plg cross-reactive Abs. The results from the NS1-immunized mouse sera indicated that NS1 immunization induced Abs that could cross-react with Plg. To study the effects of these NS1-induced Plg cross-reactive Abs on fibrinolysis, we isolated several Plg cross-reactive anti-NS1 mAbs from these mice and found that some of them could enhance Plg activation. In addition, epitope mapping with a phage-displayed random peptide library revealed that one of these mAbs (2A5) could recognize NS1 C-terminal residues 305-311, which share sequence homology with Plg residues 590-597. A synthetic peptide of NS1 residues 305-311 could inhibit the binding of both 2A5 and its Fab to Plg and its enhanced activation. Thus, our results suggest that DENV NS1 can induce Plg cross-reactive Abs through molecular mimicry, which can enhance Plg activation and may contribute to the pathogenesis of DHF/ DSS.

The nature of a particle surface has a tremendous influence on the in vitro and in vivo behavior of the particle, in addition to the particle size. In this study, multilayer modified albumin nanoparticles were developed to encapsulate teniposide, an anti-cancer agent used in the treatment of lung cancer, in order to optimize its distribution and pharmacokinetics. Multilayer nanoparticles were prepared by coating albumin particles with chitosan and subsequently with PLG-PEG. The multilayer structure was confirmed by the increase in particle size, reverse potential, surface components and morphology, suggesting a layer by layer coating mechanism, involving electrostatic interaction. According to the results of the in vitro release and cytotoxicity studies, the multilayer particles were slightly pH-sensitive to an acidic environment. More importantly, compared with the commercial injection, the modified particles showed a preference for distribution in the lung and exhibited far lower concentrations in the heart and kidney and a prolonged circulation in plasma after intravenous injection, whereas the naked albumin nanoparticles mainly accumulated in the liver and spleen. In addition, P-CS-NP with a reduced amount of PLG-PEG transiently and extensively accumulated in the lung but then rapidly migrated to the liver or spleen, suggesting that the amount of coated layer on the particles affected the targeting behavior and retention in the lung. Therefore, the structure of the albumin core and multi-coated layers are a very promising way for achieving controlled release and passively targeted delivery to the lung.