Science Forward

What if there was a way to target dysregulated signaling in one receptor while allowing five other receptors to continue normal activity? This is the question Horizon scientists asked when developing an approach to mitigate signaling through a lysophosphatidic acid receptor (LPAR).

LPAR, of which there are six types noted LPARs one to six, function through their interaction with lysophosphatidic acid (LPA), a group of molecules, that are normally involved in important cellular events, such as cell growth, migration and survival. However, in people with certain fibrotic diseases, LPA signaling via LPAR₁ is dysregulated, causing cellular damage which can lead to inflammation and fibrosis. Specifically, dysfunctional LPAR₁ signaling can cause blood vessel leakage into target tissues, damage to the protective epithelial cells that line tissues, and increased fibroblast activity, resulting in excessive collagen deposition, which can impair various organs. In the lungs, for example, excess collagen deposition limits lung expansion, ultimately restricting the ability to breathe. This can lead to diseases such as interstitial lung diseases (ILD) and cause further complications in conditions like scleroderma.

As a potential solution to this problem, Horizon R&D developed HZN-825, which specifically binds to LPAR₁. When bound, HZN-825 is thought to block pro-inflammatory and profibrotic signaling while allowing normal signaling via LPA through LPARs two through six. By selectively targeting LPAR₁ with HZN-825, our team aims to potentially inhibit disease processes that drive inflammation and fibrosis without impacting other essential LPA actions.

Horizon scientists are exploring a new approach to reducing autoimmunity that leads to diseases like lupus. Autoimmune diseases occur when the immune system mistakenly attacks the body. Recently, immune cells called plasmacytoid dendritic cells (pDCs) have been considered important players in multiple autoimmune diseases. Normally, pDCs help coordinate the immune response against viruses by producing large quantities of inflammatory cytokines, or immune signaling molecules, especially Type 1 Interferons. In certain autoimmune diseases, however, pDCs release cytokines even in the absence of an external threat, resulting in an ongoing immune response and inflammation that can damage various parts of the body.

Most research and medicine development for autoimmune diseases over the past two decades has focused on blocking the abnormal activity of two main types of immune cells: T cells and B cells. pDCs seemed an unlikely culprit since they are typically present in relatively low numbers in the bloodstream. However, their outsized ability to produce cytokines – and the presence of elevated levels of Type 1 Interferons in several autoimmune diseases – suggested they were worth a closer look.

To test this hypothesis, Horizon scientists developed a monoclonal antibody that would target ILT7, a protein found on the surface of pDCs. The team specifically designed the monoclonal antibody to bind well to ILT7 and recruit the help of other immune cells to kill pDCs with high efficiency. This therapeutic strategy was designed to deplete pDCs, thereby reducing levels of multiple cytokines involved in driving autoimmune inflammation. By targeting the source of these inflammatory molecules, this approach has the potential to interfere with underlying biological processes common to many autoimmune diseases, such as systemic lupus erythematosus, dermatomyositis, discoid lupus and alopecia. With this novel approach, Horizon hopes to address the unmet needs of a broad range of patient communities who live with autoimmune diseases.