Antibody Improves Preterm Birth Outcomes, Prevents Liver Disease in Mice

An inflammation-targeting antibody drug may help to improve two unrelated conditions – preterm birth and fatty liver disease – according to two new studies in mice, published in Frontiers in Physiology and The FASEB Journal.

Inflammation in disease

Inflammation is involved in a wide range of diseases, including autoimmune diseases, cardiovascular disease and lung diseases like asthma.

Over the last two decades, scientists in the lab of Prof. Joe G.N. Garcia, associate vice president for research at University of Florida Health, have been working on a drug designed to tackle inflammation, named ALT-100. This targets a protein called eNAMPT (extracellular nicotinamide phosphoribosyltransferase), which has a key role in inflammation and the innate immune response – the body’s first line of defense against infection.

eNAMPT activates inflammation by binding to toll-like receptor 4 (TLR4) found on innate immune cells. This triggers an inflammatory cascade designed to keep infections from moving beyond a localized area. However, the buildup of excess eNAMPT in the body’s tissues can lead to systemic inflammation, organ swelling and damage.

“The eNAMPT protein may be the most important factor in amplifying the innate immune response,” said Garcia. “When eNAMPT regulation is impaired, the results are potentially disastrous.”

In two of the group’s most recent pre-clinical studies, the researchers investigated if ALT-100 could improve outcomes from two unrelated inflammatory conditions – preterm birth related to urine infection, and non-alcoholic fatty liver disease (NAFLD) related to obesity. In both conditions, inflammation signals skyrocket, leading to worsening patient outcomes.

Potential impacts for preterm birth

Preterm birth has limited treatment options. It can be triggered by infection or inflammation, but antibiotics and anti-inflammatory medications are unable to delay delivery or prevent harm to the baby.

In their investigations, researchers found higher eNAMPT levels in blood and tissues donated by women whose pregnancies ended prematurely compared to those who delivered normally.

This was also observed in a mouse model of infection in late pregnancy. Excess eNAMPT in the placenta and amniotic sac surrounding a fetus contributed to preterm birth, resulting in reduced survival and serious disabilities in the offspring. Treating pregnant mice with ALT-100 delayed pregnancy loss and reduced disability and death in their offspring.

“Complications due to premature births, before 37 weeks gestation, are a leading cause of death worldwide among children under 5, resulting in approximately 900,000 deaths each year,” said Dr. Mohamed Ahmed, associate professor of pediatrics at the University of Arizona and lead author of the study. “This is a major unmet global medical need. Our results offer promise for this serious need.”

Mitigating liver damage

The second study investigated the role of eNAMPT in NAFLD, an obesity-related condition that causes fatigue, abdominal pain, weakness and inflammation. Fat cells in the liver secrete excess eNAMPT and metabolism becomes dysregulated, creating a vicious circle.

Mouse models of NAFLD that were treated with ALT-100 had less liver injury and fibrosis – buildup of scar tissue in the liver – than untreated mice.

Additionally, humans with metabolic syndrome and type 2 diabetes typically have elevated eNAMPT levels in their blood. When the NAFLD mouse models were fed a high-fat diet, ALT-100 reduced glucose intolerance and insulin resistance and made them less likely to develop type 2 diabetes.

“Inflammation plays a serious role in the transition from fatty liver to liver fibrosis, cirrhosis and liver cancer,” said Garcia, who is also CEO of Aqualung Therapeutics, which produces ALT-100. “We believe that the production of eNAMPT contributes to this transition, with the ALT-100 monoclonal antibody a potential therapeutic to mitigate this in a precision medicine fashion.”

Clinical trials needed to assess efficacy in humans

“Combined with our earlier studies, these results suggest that stopping the inflammatory cascade may prevent disease progression for a wide range of serious conditions with limited options, including the heartbreak of preterm birth and the difficult, protracted cascade of illnesses that flow from fatty liver disease including cirrhosis and liver cancer,” said Garcia.

ALT-100 will soon be assessed in a clinical trial of participants with acute respiratory distress syndrome (ARDS), a critical illness in patients with respiratory failure requiring mechanical ventilation.

The authors also suggest that ALT-100 may be useful for autoimmune diseases such as lupus and inflammatory bowel disease.

“I believe that our antibody is a highly novel and potentially impactful tool to address multiple serious unmet needs around the world,” Garcia said. “It will be gratifying to validate this hope in our upcoming clinical trials.”

References:

Ahmed M, Casanova NG, Zaghloul N, et al. The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes. Front. Physiol. 2023;14. doi: 10.3389/fphys.2023.1129413

Sun BL, Sun X, Kempf CL, et al. Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis. FASEB J. 2023;37(3):e22825. doi: 10.1096/fj.202201972RR

This article is a rework of a press release issued by University of Florida Health. Material has been edited for length and content.