VT-346 is a 43 kDa secreted glycoprotein that is a novel and potent inhibitor of TNF. The compound has demonstrated an extremely high affinity for human TNF. Additional studies in vitro have shown remarkable potency when compared to other anti-TNF molecules.  Of particular interest are human whole blood experiments, in which cells are stimulated and TNF levels are determined (Figure 1). VT-346 demonstrates greater suppression (10-100 times) of inflammatory responses when compared to the market leading anti-TNFs in this setting.  In addition, several studies examining mechanism of action have also yielded interesting results that are available under a confidentiality agreement with interested parties.

VT-384 (IL-18bp) is a novel secreted glycoprotein recently identified in a primate poxvirus.   Primate poxviruses have evolved to subvert the primate (human) immune system in part through the development of potent anti-inflammatory compounds.  VT-384 has been found to bind with high affinity to the human pro-inflammatory cytokine IL-18. Poxviruses have clearly borrowed from the body's attempt to regulate IL-18 activity by encoding their own version of a secreted IL-18 binding protein.

Biacore optical biosensor technology has been used to characterize binding to both human and murine IL-18 (Kd of 16 nM and 3.5 nM respectively). In addition cell-based assays have demonstrated that VT-384 was able to prevent the IL-18 stimulated induction of IFN-γ indicating an ability to interfere with IL-18 interactions with cell-surface receptors.

Preliminary pre-clinical data also demonstrates VT-384's potent in vivo anti-inflammatory effects in an inflammatory model of vascular inflammation.

VT-214 is a secreted glycoprotein that has a molecular weight of ~35 kDa, and unlike other chemokine inhibitors in development, has demonstrated an ability to bind the C-terminal heparin binding domain that is found in all three classes (C, CC and CXC) of human chemokines.  VT-214 is a potent inhibitor of inflammatory cell recruitment and is active in vivo at extremely low doses in rabbit, mouse, and rat models of inflammation, including balloon angioplasty induced restenosis, solid organ (renal) transplant, and aortic allograft transplant.  VT-214 reduces vascular inflammation as measured by a reduction in both intimal hyperplasia and monocyte/macrophage infiltration into the sites of injury.

Recent studies have confirmed that chemokine oligomerization and binding to glycosaminoglycans are essential for their activity in vivo.  Binding of the glycosaminoglycan heparin to chemokines has been found to interfere with the binding of VT-214.  In addition, chemokine analogues lacking a heparin-binding domain were no longer able to bind to VT-214 in vitro.  Therefore, it is thought that by interfering with the chemokine gradient formation, VT-214 can neutralize the activity of a broad range of chemokines. VT-214 was found to reduce the total number of infiltrating macrophages and T-cells after peritoneal chemokine administration (MCP-1) induced leukocyte recruitment in a mouse model.

VT-310 is a novel secreted glycoprotein recently identified in the genomes of the primate poxviruses that have evolved to subvert the primate (human) immune system.  VT-310 is a homologue of human IL-10.  IL-10 is one of the body's natural mechanisms used to limit, and ultimately terminate, an ongoing inflammatory response. IL-10 suppresses T-cell responses directly by reducing T cells production of IL-2, TNF- α and IL-5, and indirectly suppresses T-cell response by inhibiting antigen presentation by reducing the expression of MHC and co-stimulatory molecules by antigen presenting cells.

VT-362 has been shown to bind CD153 on the surface of human neutrophils, thereby preventing interactions between intact cellular CD30 and CD153.  Early preclinical studies demonstrated VT-362 has the ability to inhibit T-cell activation in vitro, and to prevent the induction of a type 1 (TH1) T-cell response in vivo.