Advancing Therapies for Autoimmune Disease Via Shared Critical Pathways

Autoimmune diseases arise when a person’s immune system launches an attack against one’s own healthy cells and tissue. Several factors impact the genesis of autoimmune disease, but most therapies today focus on alleviating symptoms rather than addressing the cause. At Viela, we seek to redefine the treatment of autoimmune diseases by focusing on critical biological pathways shared across multiple diseases, permitting us to develop novel and more precisely targeted treatments. We are currently focused on three pathways: the autoantibody pathway, the CD40/CD40L co-stimulatory pathway and the innate cytokine pathway.

Autoantibody Pathway

Autoantibody Pathway

Inebilizumab is designed to bind to CD19, a cell surface molecule broadly expressed on B cells, initiating B cell depletion. This depletion stops autoreactive B cells from differentiating into antibody-secreting plasmablasts and plasma cells, which may decrease the production of pathogenic autoantibodies and therefore, the autoimmune response.

CD40/CD40L Co-stimulatory Pathway

VIB4920 is designed to bind to CD40L on activated T cells, blocking CD40L’s interaction with CD40-expressing B cells. Inhibiting CD40/CD40L interaction prevents B cells from differentiating into plasmablasts and plasma cells, potentially resulting in powerful immunomodulation for targeting T and B cell-driven autoimmune diseases.

Innate Cytokine Pathway

VIB7734 is designed to target and bind to ILT7—a cell surface molecule specific to plasmacytoid dendritic cells (pDCs)—causing apoptosis, or cell death. pDCs generate inflammatory cytokines, such as type I interferons, TNF-α and IL-6, in pathological states. As a result, the depletion of pDCs may decrease the production of inflammatory mediators involved in autoimmune diseases.

The Autoantibody Pathway

Production of Autoantibodies

When immune system B cells, known as plasmablasts and plasma cells, become autoreactive and the mechanisms that normally eliminate or suppress these cells fail, autoantibodies are created. In autoimmune disease, these autoantibodies become pathogenic and attack one’s body as opposed to foreign pathogens, causing inflammation. A number of autoimmune diseases, including NMOSD, myasthenia gravis and IgG4-related diseases, as well as conditions like kidney transplant rejection, are associated with the autoantibody pathway.

Inebilizumab is designed to bind to CD19, a cell surface molecule broadly expressed on B cells, initiating B cell depletion. This depletion stops autoreactive B cells from differentiating into antibody-secreting plasmablasts and plasma cells, which decreases the production of pathogenic autoantibodies, lessening the autoimmune response.

The CD40/CD40L Co-stimulatory Pathway

Immune Activation through
Co-Stimulatory Pathways

T cells interact with a range of immune cells through various co-stimulatory receptor-ligand interactions. The CD40/CD40L interaction plays a critical role in driving humoral immune responses and has been linked to autoimmunity. In fact, their interaction can result in the overstimulation of T and B cells, producing an immune response cascade and overproduction of molecules that stimulate inflammation. Several autoimmune diseases, such as Sjögren’s syndrome, systemic lupus erythematosus (SLE), type 1 diabetes and conditions such as kidney transplant rejection, are associated with the overactivation of the CD40/CD40L co-stimulatory pathway.

VIB4920 is a fusion protein designed to bind to CD40L on activated T cells, blocking CD40L’s interaction with CD40-expressing B cells and potentially other binding partners. Thus, VIB4920 is designed to block autoimmune and inflammatory responses by preventing B cells from differentiating and inhibiting the stimulation of dendritic cells and monocytes. These combined effects have the potential to produce powerful immunomodulation for targeting both T and B cell-driven diseases.

The Innate Cytokine Pathway

Overactivation of the Innate
Immune System

When specialized innate immune cells—called plasmacytoid dendritic cells (pDCs)—recognize and become activated by viral infections or immune complexes, the production of large amounts of cytokines can occur. In addition to the production of cytokines, pDCs also help activate other arms of the immune system, including T cells and B cells. The overproduction of innate cytokines such as type I interferons, IL-6 and TNFα—in addition to activation of the immune system—may trigger autoimmunity. A number of autoimmune diseases including cutaneous lupus erythematosus (CLE), SLE, Sjögren’s syndrome, systemic sclerosis, polymyositis, and dermatomyositis are associated with the overproduction of pro-inflammatory cytokines secreted by pDCs.

VIB7734 is designed to target and bind to an immunoglobulin-like transcript, (ILT7)—a cell surface molecule specific to pDCs—causing recruitment of macrophages and natural killer cells to induce apoptosis. The pDCs generate the majority of type I interferons in pathological states, and the depletion of pDCs may decrease the production of this pro-inflammatory stimuli in addition to other inflammatory cytokines, such as TNF-α and IL-6. We believe that this novel candidate has the potential to treat autoimmune diseases where the pathology is driven primarily by the overproduction of cytokines.