Phosphatase-activating antibody for cutaneous lupus therapy

Cutaneous lupus erythematosus (CLE) is a common autoimmune disease of the skin that results in inflammation, scarring, or the formation of coin-shaped lesions called discoid lesions. CLE may occur in patients with systemic lupus erythematosus (SLE) or as a standalone skin disease. Disease in CLE is driven primarily by two cell types: plasmacytoid dendritic cells (pDCs), which contribute to inflammation, and skin fibroblasts, which contribute to scarring of the skin. Current treatment standards include the use of corticosteroids or antimalarial drugs, but even so, several patients do not fully respond to treatment. Moreover, most current lupus therapies act by solely targeting the inflammatory action of pDCs, leaving the skin fibroblasts untreated. We have identified a new protein of interest for developing a new drug that would block the problematic activity of both pDCs and skin fibroblasts in CLE patients.

In CLE, such protein is inactivated, leading to inflammation and scarring of the skin. To address this, our team has developed an antibody that specifically activates the protein, thus reducing the inflammatory action of pDCs and scar tissue formation by skin fibroblasts. Early results with this antibody have shown efficacy in blocking the release of inflammatory signal molecules (called cytokines) from pDCs and reducing expression of markers involved in scar tissue formation. As part of these initial findings, treatment with the antibody proved effective in a mouse model of lupus as evidenced by a lower autoimmune response and reduction in lupus symptoms of the skin. The team will now focus on developing the antibody further as a potential therapy approved for progression to clinical trials.

The objective of this proposal is to develop an antibody targeting the receptor protein tyrosine phosphatase sigma (phosphatase) as a new biologic therapy for cutaneous lupus erythematosus (CLE). CLE is a complex autoimmune skin disease that occurs as a manifestation of systemic lupus erythematosus or as an isolated skin disease. The most common type of CLE is discoid lupus erythematosus (DLE), which causes major scarring and disfigurement. There are only a few treatment options for CLE, and roughly half of patients do not adequately respond. Ongoing clinical trials are showing promising results for drugs that inhibit plasmacytoid dendritic cells (pDCs) -the major inducers of the type 1 interferon response that is a hallmark of lupus- or directly target the type 1 interferon receptor. Importantly, however, no drug addresses the action of skin fibroblasts -cells that play a major role in scarring- for CLE or any other indication.

We identified a transmembrane phosphatase as a novel target for inhibiting both pDCs and skin fibroblasts in CLE. Phosphatases tend to inhibit signal transduction by counterbalancing the action of protein tyrosine kinases. The phosphatase is expressed in fibroblasts and pDCs, while it is absent in all other immune cells. The activity of the phosphatase is regulated through a known molecular mechanism.

We developed an antibody that activates the phosphatase and inhibits signaling in both pDCs and fibroblasts, leading to reduced pDC production of type 1 IFN and inflammatory cytokines, and reduced pro-fibrotic responses of fibroblasts. Importantly, administration of this antibody significantly reduces lupus symptoms in mice. Several rounds of maturation have led to a high affinity derivative with exquisite selectivity for the phosphatase.

The goal of this project is to accomplish key steps in the development of the lead phosphatase-activating antibody towards clinical trials. The aims are to perform 1) developability studies of the lead antibody and 2) efficacy studies of the lead in treating lupus skin pathology in a mouse model, and 3) to develop pharmacodynamic markers of phosphatase activation. While carrying out this project, we will also develop a robust regulatory strategy for progression of this drug into clinical trials for CLE.

In summary, this project has tremendous potential to impact patient care for CLE for providing a therapy that will offer both the immunoregulation and skin fibroblast inhibition needed to treat inflammation, damage, and scarring in CLE.