What is the eNAMPT-Neutralizing ALT-100 mAb
Discovery of eNAMPT as a therapeutic target in inflammatory and fibrotic disease. The seminal scientific discovery underlying the Aqualung Therapeutics portfolio made when Dr. Garcia (CEO) was Chief of Pulmonary and Critical Care Medicine at Johns Hopkins University School of Medicine. The Garcia laboratory advanced a functional genomic research program designed to identify novel candidate genes involved in contributing to the morbidity and mortality of serious inflammatory and fibrotic disorders such as ARDS, pulmonary fibrosis and pulmonary hypertension (see Figures below) and identified nicotinamide phosphoribosyltransferase (NAMPT) as a highly novel candidate gene in a number of inflammatory and fibrotic diseases.
An example of the genomic strategies utilized to identify the NAMPT gene encoding extracellular nicotinamide phosphoribosyltransferase in preclinical models of ARDS and VILI.
Another example of the genomic strategies in a canine model of ARDS/VILI utilized to identify the NAMPT gene encoding extracellular nicotinamide phosphoribosyltransferase in preclinical models of ARDS and VILI (in publications PMID: 15579727 and PMID: 16782753.
NAMPT encodes eNAMPT which Aqualung scientists have shown to serve as a key biomarker in inflammatory and fibrotic conditions such as Acute Respiratory Distress Syndrome (ARDS), sepsis, idiopathic pulmonary fibrosis, pulmonary hypertension, systemic lupus erythematosus, non-alcoholic liver disease, and prostate cancer. More importantly, we demonstrated that eNAMPT is a powerful damage -associated molecular pattern protein which is a major regulator of innate immunity via eNAMPT bindng to the key pathogen recognition receptor, Toll-like Receptor 4 (TLR4). The triggering of theeNAMPT/TLR4 signaling cascade produces the potent release of NFkB-dependent inflammatory and fibrotic mediators which directly influence the severity of the disease.
Of critical importance, Aqualung Therapeutics has now developed a a “First in Man” immune-based humanized monoclonal antibody (mAb), ALT-100, to inhibit eNAMPT binding to TLR4 (see Figure below). The ALT-100 mAb is designed to prevent the development of “unchecked inflammation” and progressive fibrosis in a number of severe inflammatory diseases, thereby addressing important medical and societal unmet needs. ALT-100 is a novel and potential game-changing therapy for many inflammatory conditions such as Acute Respiratory Distress Syndrome, Ventilator Induced Lung Injury, Radiation Induced Lung Injury, Chorioamnionitis, Prostate Cancer, Pulmonary Hypertension and Pulmonary Fibrosis.
Generation of ALT-100 mAb
Click on the below indications to view relevant publications demonstrating the efficacy of ALT-100 mAb in preclinical models of ARDS/Ventilator Induced Lung Injury, pulmonary hypertension, prostate cancer, systemic lupus lung vasculitis, radiation-induced lung injury more
Lead Clinical Indications for ALT-100 mAb. Aqualung Therapeutic’s lead acute indication is for the treatment and prevention of Acute Respiratory Distress Syndrome (ARDS)/ Ventilator Induced Lung Injury (VILI). Delivered intravenously at he time of mechanical ventilation initiation, ALT-100 neutralizes circulating eNAMPT, thus reducing the potential for development of unchecked inflammation that affect the 40% mortality of ARDS/VILI. 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.
The lead chronic clinical indications for the ALT-100 mAb is radiation-induced pneumonitis and fibrosis and pulmonary hypertension. The ALT-100 mAb can be delivered subcutaneously at the time of initiated radiotherapy to prevent the develop of radiation lung toxicity. Current FDA approved drugs for pulmonary fibrosis are weak, poorly tolerated and only slow the decline in lung function. Our data indicate the mAb can to halt the progression of fibrosis and in the setting of radiation, prevent the development of fibrosis.
Similarly, ALT-100 mAb can be delivered subcutaneously to halt the progression of pulmonary hypertension ad potentially reverse the severity of disease.
