General

Secretoglobins (SCGBs) are naturally occurring proteins produced in the body by various organs. The SCGBs produced in the lungs are some of the most abundant proteins secreted in the airways. Naturally occurring SCGB1A1 is the most abundant protein in the fluid that lines the respiratory tract, including the nasal airways. These proteins modulate inflammatory and immunologic responses to the environment on mucosal surfaces throughout the body.

Respiratory tract damage and lung impairment can be caused by numerous insults, including infectious pathogens, allergens, dust or smoke, chemicals, noxious gases, inert particles, and many other potential irritants. When lungs are exposed to these insults, an inflammatory response is triggered, which often causes more physical damage to the lungs, leading to acute lung injury, loss of lung function, and/or long term fibrosis.

Many patients with acute or chronic respiratory conditions are deficient in their own SCGB1A1 production due to a paucity of airway epithelial cells, called Club cells, that produce SCGB1A1 and populate normal airways. In chronic rhinosinusitis, the nasal airway cells that produce SCGB1A1 are replaced by fibrotic cells and scar tissue, resulting in a deficiency of SCGB1A1 and normal airway epithelial cells which pre-disposes patients to persistent infections and further scarring, eventually requiring sinus surgery. Similarly, in acute lung injury due to influenza-like illness, smoke inhalation, or sepsis, the normal lung epithelial cells are damaged, resulting in loss of local SCGB1A1 production. The administration of rhSCGB1A1 in these conditions reduces viral load, reduces inflammation, protects lung function, stimulates repair, and reduces fibrosis in the lungs. In COPD, there is also a well-characterized deficiency of Club cells and the SCGB1A1 protein in the lungs. Many other respiratory conditions also have been associated with a deficiency of Club cells and native SCGB1A1. rhSCGB1A1 may prove to help alleviate this cascade of potential injuries through its anti-inflammatory effects as well as its potential to stimulate lung repair.

Our therapeutic pipeline is derived from a family of proteins referred to as secretoglobins. We are developing two different secretoglobin proteins, SCGB1A1 and SCGB3A2, which are produced predominately by cells lining the epithelial surface of the respiratory tract. These secretoglobins have been extensively studied and characterized and they are highly conserved as a result of the central role they appear to play in airway homeostasis and repair. We have also developed a next generation high potency version of rhSCGB1A1, which is essentially an “activated” version of the original molecule that will enable the application of the technology to much larger respiratory patient populations using an inhaled route of administration.

Our main candidate for clinical development is the SCGB1A1 protein, also known as the Club Cell 10 kilodalton protein (CC10), Club Cell Secretory Protein (CCSP), CC16, and uteroglobin. SCGB1A1 is primarily secreted by Club Cells which have historically been called Clara Cells and CCSP-positive cells. SCGB3A2 is also referenced in the scientific literature as Uteroglobin Gene Related Protein 1 (UGRP1).

Impact on Lung Inflammation

At least four distinct pathways are affected by SCGB1A1:

1) Phospholipase A2 (PLA2) are enzymes found in many tissues that catalyze the hydrolysis of glycerophospholipids to release arachidonic acid (AA). AA is a substrate for a variety of other enzymes that lead to the formation of eicosanoid mediators of inflammation, such as leukotrienes, which have been linked to development of neonatal lung disease and are associated with severity and progression of chronic lung diseases in adults, including COPD and asthma. SCGB1A1 and SCGB3A2 inhibit PLA2 enzymes.

2) The influx of neutrophils to the lungs of individuals with Respiratory Distress Syndrome (RDS) or with chronic lung disease contributes to life-threatening inflammation and loss of lung function. Interleukin 6 (IL-6), a chemotactic agent that is released by cells within the damaged lung, attracts white cells from the blood, particularly neutrophils. SCGB1A1 and SCGB3A2 inhibit neutrophil influx to the lungs and SCGB1A1 suppresses IL-6.

3) Nuclear factor kappa B (NF-kB) is a master molecular switch that can turn on multiple inflammatory pathways in the lung and in many other tissues. NF-kB normally is dormant in the cytoplasm of a cell. When a cell experiences an insult or receives a pro-inflammatory signal from another cell, NF-kB is activated, translocates into the cell nucleus, and increases the transcription of additional pro-inflammatory regulators. SCGB1A1 suppresses the activation of NF-kB, both in vitro and in vivo and thereby suppresses inflammation and the fibrosis caused by triggering of the NF-kB signal transduction pathway.

4) Another aspect associated with RDS and acute lung injury is increased vascular permeability, which results in pulmonary edema. Pulmonary edema is life-threatening with limited treatment options at this time. SCGB1A1 reduces vascular permeability in acute lung injury, minimizing pulmonary edema.

SCGB3A2 mimics the PLA2-inhibiting and neutrophil inhibiting properties of SCGB1A1, reduces fibrosis and has additional properties against cancer cells.