VT-346 is a 43 kDa secreted glycoprotein that is a novel and potent inhibitor of human TNF-α.  In pre-clinical testing, the compound has demonstrated an extremely high affinity for human TNF-α, in the order of 10-25 times that of some currently marketed anti-TNF therapies.  The gene was isolated, cloned into a baculovirus expression system, and small amounts of the recombinant protein were purified and examined for binding activities using Biacore analysis.  It was confirmed that the viral TNF-binding protein (TNF-bp) was able to bind human TNF-α with very high affinity (Table 1).

Preliminary in vivo data in a model of vascular inflammation also demonstrates potent drug effects at extremely low doses.

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.  Importantly, in a mouse model where peritoneal chemokine administration (MCP-1) induces leukocyte recruitment, VT-214 was found to reduce the total number of infiltrating macrophages and T-cells.

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-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 by inhibiting antigen presentation by reducing the expression of MHC and co-stimulatory molecules by antigen presenting cells.

VT-224 is a secreted 43 kDa glycoprotein that is a member of a larger family of poxvirus chemokine binding proteins called the M-T1/35K family that binds specifically to the CC-class of chemokines thereby preventing CC-chemokine receptor stimulation. VT-224 has demonstrated affects on the regulation of infiltrating leukocytes into sites of infection, an ability to disrupt macrophage migration and inhibition of chemotaxis both in vitro and in vivo.

Early in vivo characterization of VT-224 has demonstrated a potent ability to reduce vascular inflammation at low doses (ng-pg) in an aortic allograft transplant model.  VT-224 was active in reducing intimal hyperplasia, monocyte/macrophage and CD2 positive T-cell infiltration into sites of injury.

VT-362 (CD30) is a 12kDa novel secreted protein.  Viruses have numerous immune evasion strategies including proteins that mimic cellular cytokines and receptors and interfere with the generation of inflammatory signals.  As an example, VT-362 is a viral homologue of the cellular protein CD30, and has demonstrated binding to the ligand for CD30 called CD153 found on the cell surface of some lymphocytes.  VT-362 is unique in has the potential to affect lymphocyte function directly.  Initial work suggests that VT-362 can reduce T-cell activation and inhibit the production of pro-inflammatory cytokines.  Early in vivo pre-clinical testing has demonstrates VT-362's ability to significantly reduce cytokine expression and lesion formation (granuloma) in a lung inflammatory model. This ability to alter TH1 type responses in vivo highlights its potential in autoimmune diseases.

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 of VT-362 have demonstrated an ability to inhibit T-cell activation in vitro, and to prevent the induction of a type 1 (TH1) T-cell response in vivo.