AVTX-002 is a fully human monoclonal antibody, directed against human LIGHT (Lymphotoxin-like, exhibits Inducible expression, and competes with Herpes Virus Glycoprotein D for Herpesvirus Entry Mediator (HVEM), a receptor expressed by T lymphocytes). AVTX-002 is currently in Phase 2 development for non-eosinophilic asthma (NEA) with proof-of-concept data in inflammatory bowel diseases (IBD) and COVID-19 acute respiratory distress syndrome (ARDS).

Targeting LIGHT

LIGHT is a newly recognized cytokine with inflammatory actions encoded by the TNFSF14 gene. LIGHT plays an important role in regulating immune responses in the lung, gut, and skin and is “upstream” (or proximal) in the inflammatory cascade to many well recognized cytokines like interleukin (IL)-1, IL-6, IL-10, IL-13, tumor necrosis factor (TNF), and granulocyte-macrophage colony-stimulating factor (GM-CSF).

CXCL5, C-X-C motif chemokine 5; DcR3, decoy receptor 3; DR3, death receptor 3; FasL, Fas ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; HVEM, herpesvirus entry mediator; IL, interleukin; LTßR, lymphotoxin-ß receptor; TL1A, TNF-like ligand 1A; TNF, tumor necrosis factor.

ARDS is a serious condition that causes changes to the lungs resulting in low blood oxygen. Insufficient oxygen in the bloodstream and throughout the body can result in severe organ damage. Lung scarring can also occur. ARDS can worsen quickly and may be life-threatening.

Compared with other cytokines, LIGHT has a unique dual mechanism of action, exerting its effects by activating both T cells and B cells, as well as upregulating other inflammatory cytokines. LIGHT, like many cytokines, appears to be involved in the dysregulated immune response, or “cytokine storm” implicated in ARDS. Secreted by neutrophils, macrophages, and other inflammatory cells during an immune system response to infection, LIGHT has been shown to play a key role in viral pneumonia and has been implicated in promoting fibrosis (scarring) in the lung after infection.

Significant opportunity remains for treatments affecting novel targets in moderate to severe IBD. Approximately one-third of patients are primary non-responders to tumor necrosis factor inhibitors (anti-TNFs), and 30-50% of initial responders become refractory. Remission rates for advanced therapies have remained at ~20% (placebo-adjusted) for patients with moderate to severe disease.

Transgenic expression of LIGHT on T cells in mice has been shown to promote inflammation in multiple organs, including the intestine. In addition, LIGHT gene upregulation and elevated levels of LIGHT have been observed in patients with Crohn’s disease and ulcerative colitis, suggesting a potentially important role in the pathogenesis of IBD.

Attributes of AVTX-002

  • Novel mechanism of action
  • Potential to be first in class
  • Fully human monoclonal antibody
  • Novel Free-LIGHT assay for biomarker-enabled development
  • Subcutaneous dosing