When Dr. Joe G.N. “Skip” Garcia, M.D., was director of pulmonary and critical care medicine at Johns Hopkins University, his laboratory identified NAMPT (nicotinamide phosphoribosyltransferase) as a master regulator of inflammation and innate immunity.
Inside the cell, NAMPT is an enzyme that plays a crucial role in the biosynthesis of nicotinamide adenine dinucleotide (NAD), an essential molecule involved in various biological processes such as energy metabolism, DNA repair, and cell signaling. NAMPT converts nicotinamide (NAM) into nicotinamide mononucleotide (NMN), which is then used to generate NAD, which is essential for cellular health and preventing senescence.
This important cellular function is in contrast to NAMPT effects when it is secreted into the bloodstream, the extracellular form is known as eNAMPT. Garcia lab has found that eNAMPT is a master regulator of innate immunity affecting many pro-inflammatory genes and proteins that participate in the inflammatory response. eNAMPT is a DAMP, or damage-associated molecular pattern protein, released from injured tissues and via binding to a key and powerful pathogen recognition receptor, Toll-like Receptor 4 (TLR4), to trigger the inflammatory response. Among the many DAMPs, eNAMPT is one of the most important DAMPs in amplifying the innate immune response. When regulation of eNAMPT levels is impaired, the excessive blood levels of eNAMPT leads to profound and potentially disastrous systemic inflammation, organ damage and even cytokine storm. This hyperimmune reaction is responsible for many deaths from COVID-19 during the pandemic. Importantly eNAMPT is a druggable target and the center has developed a humanized monoclonal antibody to block eNAMPT inflammatory activity, called ALT-100 mAb.
A Novel Therapeutic Monoclonal Antibody Neutralizes Excess NAMPT
In partnership with the biotech company, Aqualung Therapeutics Corporation, CISSM scientists have developed a “first in man” immune-based humanized monoclonal antibody (mAb), known as ALT-100. ALT-100 is designed to address the development of unchecked inflammation in a number of severe inflammatory diseases. ALT-100 works through binding the TLR4 receptor, which scientists have, in the past, tried block in order to stop inflammation. Unfortunately, that strategy failed in clinical trials because blocking TLR4 suppressed the patients’ ability to fight infection or sepsis. The eNAMPT-neutralizing ALT-100 mAb does not block TLR4 thus allowing the TLR4 to continue with its protective function against infection with an indirect route to the same goal of suppressing inflammation.
The antibody has already passed a first safety clinical trial phase in healthy human volunteers with no serious adverse events identified. In an upcoming Phase 2 clinical trial called PUERTA, ALT-100 mAb will tested in subjects with acute respiratory distress syndrome (ARDS), a critical illness in patients with respiratory failure requiring mechanical ventilation with a 40% mortality rate. In addition to ARDS, in published studies the CISSM scientists have shown that the ALT-100 mAb has dramatic beneficial effects in reducing inflammation and fibrosis in diverse disorders ranging from pregnant women with intrauterine inflammation and fibrosis resulting in preterm births, to patients with autoimmune disease such as systemic lupus and inflammatory bowel disease, pulmonary fibrosis, pulmonary hypertension and even cancer.
ALT-100 mAb Effects on Preterm Births
For subacute and chronic disorders, ALT-100 can be delivered at the time of initiated radiotherapy, or at the time of transition from indolent to metastatic prostate cancer. This approach distinguishes ALT-100 therapy from the many failed drugs that targeted a single cytokine (i.e. TNF-a, IL-1b, IL-6 etc.) which were delivered after the presence of established lung injury and inflammation. Because levels of multiple cytokines are already markedly elevated, a process known as “cytokine storm”, these single cytokine-directed therapies were ineffective in reducing inflammation. In the absence of newer therapies focused exclusively on unchecked inflammation, and with unacceptable ICU mortality rates ALT-100 mAb therapy will create a new market and is expected to improve outcomes, reduce healthcare costs, save lives and provide cost savings to hospitals and insurers.
Complications due to premature births, before 37 weeks gestation, are a leading cause of death among children under five, resulting in approximately 900,000 deaths each year, highlighting a major unmet global medical need. Doctors currently have limited options when a pregnant women goes into labor prematurely due to infection or inflammation. Antibiotics or anti-inflammatory drugs may be prescribed, but that fails to stop the premature delivery or prevent complications in the preterm baby. CISSM scientists have documented high levels of eNAMPT in blood and tissues from women whose pregnancies had ended prematurely with preterm births, relative to infants delivered after full nine-month pregnancy. Similar elevation in plasma eNAMPT levels was observed in blood and tissues from pregnant mice with uterine inflammation. Their data showed that excess eNAMPT in the placenta and amniotic sac surrounding a fetus contributed to preterm birth, resulting in reduced survival in the offspring who later exhibit serious disabilities. Treatment of the pregnant mice with the eNAMPT-neutralizing ALT-100 antibody delayed the pregnancy loss and reduced disability and death in their offspring, a study published June 20 in the journal Frontiers in Physiology. In untreated pregnant mice with uterine inflammation, all babies were born prematurely, with 80% dead on delivery. In pregnant mice with uterine inflammation, mice receiving the ALT-100 mAb, 80% were alive. These results clearly demonstrate that eNAMPT is a highly druggable target involved in the complications of premature births. CISSM research results offer promise for addressing this serious unmet need.
ALT-100 mAb Effects on Obesity-Related Fatty Liver Disease and Liver Fibrosis
CISSM scientists recently studied the role of eNAMPT in fatty liver disease. Up to one quarter of adults have excess fat in their livers. It is an obesity-related condition that causes fatigue, abdominal pain, weakness and initiates inflammatory processes. As metabolism becomes dysregulated, fat cells in the liver secrete excess eNAMPT, promoting a vicious spiral of illness. Inflammation plays a serious role in the transition from fatty liver to liver fibrosis, cirrhosis and liver cancer. The production of eNAMPT contributes to this transition, with the ALT-100 mAb a potential therapeutic to mitigate this in a precision medicine fashion. Four in 10 people diagnosed with fatty liver disease may go on to develop a more serious condition, NASH, short for non-alcoholic steato-hepatitis. It’s a step on the road to liver fibrosis and cirrhosis, where scar tissue replaces healthy liver tissue. Fatty liver disease increases risk of heart disease, liver cancer, type 2 diabetes and chronic kidney disease. In mouse models of non-alcoholic fatty liver disease, mice treated with the monoclonal antibody ALT-100 experienced less liver injury and fibrosis than untreated mice.
Those fed a high-fat diet and treated with ALT-100 also had reduced glucose intolerance and insulin resistance, and were less likely to develop type 2 diabetes.
In human subjects with metabolic syndrome and type 2 diabetes, eNAMPT was found to be significantly elevated in blood plasma.
Non-alcoholic fatty liver disease is a major public health issue world-wide with approximately 40% of patients progressing to NASH and subsequently to liver fibrosis and cirrhosis. CISSM research indicates that eNAMPT inflammatory pathway activation is a key contributor to non-alcoholic fatty liver disease and progression to hepatic fibrosis. With so many adults living with some degree of fatty liver disease, it becomes important to understand who would benefit from treatment with ALT-100. This is preventable disease with the right therapeutic. Given the global pandemic in people affected by NASH and metabolic syndrome, we need precision medicine approaches with useful biomarkers and genetic testing to identify folks who are most likely to benefit from treatment. The Center for Inflammation Science and Systems Medicine is working hard on developing these tools.
The Center for Inflammation Science and Systems Medicine and Precision Medicine Platforms
To more strategically identify patients most likely to respond to ALT-100 mAb, and potentially increase the probability of clinical trial success, Center scientists have developed eNamptorTM, a precision medicine platform. The functional proteomic /genomic platform consists of three components, including the highly preclinically effective mAb first-in-class humanized mAb targeting eNAMPT, ALT-100, which blocks eNAMPT/TLR4- mediated runaway inflammation and fibrosis. The second component is a plasma-based eNAMPT biomarker assay which is based upon the observation that plasma eNAMPT levels are significantly elevated in ARDS subjects and are linked to ARDS severity (mortality).The third platform component is a NAMPT genotyping assay derived from compelling genetic studies in ARDS subjects. It identified two high-risk single nucleotide polymorphisms to the NAMPT gene that confer increased risk of ARDS and mortality. Thus, both the biomarker and genotyping components of the eNamptorTM platform predicts the severity/mortality of inflammatory and fibrotic disorders, and identifies potential ALT-100 mAb responders in a variety of acute and chronic inflammatory disorders where eNAMPT plays a major role in driving the severity of the disease.