Antibody – VX15 Multiple Sclerosis
Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration, localized myelin destruction, and neural cell demise (1;2). Given the debilitating nature of the motor and sensory dysfunction associated with MS, there exists a significant need to identify novel therapeutic targets and strategies that safely and effectively slow progression and even reverse this disease. One promising target for MS therapeutic development is semaphorin 4D (SEMA4D). Signaling cascades initiated by SEMA4D induce T cell (3), B cell (4), and microglial activation (5), neuronal process collapse, apoptosis and decreased maturation of oligodendrocyte precursor cells [OPC; (6)].
To efficiently target SEMA4D, we have generated a humanized monoclonal antibody, VX15/2503, which recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cellular receptors. In vitro, VX15/2503 prevents SEMA4D-induced actin cytoskeleton collapse (Figure 1), and reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, we have demonstrated that a mouse monoclonal antibody (MAb 67-2), which binds to the same epitope as VX15/2503, significantly attenuates disease severity in multiple preclinical models of MS [experimental autoimmune encephalomyelitis (EAE); Figure 2], reduces infiltration and activation of macrophage/microglial cells (Figure 3), preserves the integrity of the blood-brain barrier, and improves myelination status (Figure 4).
Taken together, our observations highlight SEMA4D as a key factor in multiple neuroinflammatory disease-related processes and support the further development of VX15/2503 as a novel therapeutic strategy for MS and other neuroinflammatory/neurodegenerative diseases. To that end, enrollment has been initiated in a Phase I, multicenter, randomized, double-blind, placebo-controlled, ascending single-dose study of the safety, tolerability, and pharmacokinetics of intravenous anti-SEMA4D (VX15/2503) in patients with MS.
VX15/2503 - Vaccinex is currently conducting a Phase I clinical trial of VX15/2503 monoclonal antibody in adult patients with Multiple Sclerosis. This is a single-dose trial measuring safety and tolerability. For further information and eligibility criteria, please refer to the National Institutes of Health ClinicalTrials.gov Web site listed below.
Figure 1. Anti-SEMA4D rescues oligodendrocyte precursor cells (OPC) from SEMA4D-induced cytoskeletal collapse. Oligodendrocyte precursor cells (OPCs) were established and treated with control protein (C35), 50 µg/ml recombinant SEMA4D alone, 50 µg/ml SEMA4D + 500 µg/ml control IgG (MAb 2955), or 50 µg/ml SEMA4D + 500 µg/ml anti-SEMA4D antibody (VX15/2503). Cells were fixed with 4% PFA and cytoskeletal changes were visualized by Phalloidin-A488 staining.
Figure 2. The anti-SEMA4D antibody 67-2 is able to reduce disease severity in a peptide-based mouse model of multiple sclerosis.
6 to 8 week old SJL mice were administered a combination of PLP peptide 139-151 in CFA to induce disease. Mice were given 600ugs of a negative control mouse IgG antibody or of antibody 67-2 intraperitoneally starting at day 7. Dosing continued 1X per week for a total of 6 doses. Comparing with the IgG control, 67-2 treatment reduces group mean score by 53%. Experiment has been repeated four times with similar results.
Figure 3. Inflammatory cell infiltrates are less severe in spinal cords of anti-SEMA4D-treated EAE mice. TH1-polarized T cells from PLP139-151/CFA emulsion-immunized mice were adoptively transferred into SJL mice, followed by periodic intraperitoneal administration of control IgG (MAb 2B8) or anti-SEMA4D antibody (MAb 67-2) starting on day 10. Mice were sacrificed on day 24 post-adoptive transfer, and spinal cords were processed for immunohistochemical analyses of resident and infiltrating immune cells. Immunohistochemistry was performed for macrophages/microglia using an anti-F4/80 antibody. F4/80-positive cells are brown in color.
Figure 4. Anti-SEMA4D treatment leads to improved myelination integrity in the setting of EAE. To determine the effects of anti-SEMA4D antibody treatment on myelination status, myelin ultrastructure in spinal cords of rats induced to develop EAE was examined by electron microscopy. Coronal spinal cords from control IgG and anti-SEMA4D-treated animals were post-fixed in 1.0% osmium tetroxide, dehydrated, and embedded in Epon. Ultra-thin sections were counterstained with uranyl acetate followed by lead citrate and examined using a transmission electron microscope. Myelinated axons are labeled with an “Ax”.
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