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).
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.
LIGHT has been implicated as a key driver of asthma by mechanistic studies in preclinical animal models and relevant cell culture systems. Human data has demonstrated elevated levels of LIGHT and the HVEM receptor in peripheral blood of asthmatic subjects that correlates with the severity of airflow obstruction.
Asthma is a chronic disease of the lungs characterized by airway inflammation causing swelling and excess mucous production. Asthma is classified as eosinophilic or non-eosinophilic, with 50% of severe asthma cases related to NEA. Many patients with NEA respond suboptimally to standard asthma treatments, especially to inhaled corticosteroids. This can lead to a higher severity of disease and more difficult-to-control asthma, which can be life-threatening for some patients. Blocking LIGHT protein signaling will potentially inhibit proinflammatory and profibrotic pathways directly relevant to asthma pathogenesis. Avalo is currently studying AVTX-002 in NEA patients (PEAK Trial).
COVID-19 induced 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. Avalo has completed a trial in COVID-19 induced ARDS where benefit was demonstrated (Perlin DS et al., Randomized, double-blind, controlled trial of human anti-LIGHT monoclonal antibody in COVID-19 acute respiratory distress syndrome. J Clin Invest. 2022;132(3):e153173.[LHP1] [JZ2])
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.