General

Secretoglobins are naturally occurring proteins produced in the body by Club Cells. They are some of the most abundant proteins secreted in the airways. Naturally occurring CC10 is the most abundant protein in the fluid that lines the respiratory tract in both the upper and lower lung, including the sinus cavities. These proteins modulate inflammatory and immunologic responses to the environment on mucosal surfaces throughout the body. The CC10 family of proteins share a conserved dimeric structure.

Respiratory tract damage and lung impairment can be caused by numerous insults, including infectious pathogens, allergens, dust or smoke, chemicals, gases, inert particles, and many other potential irritants. When lungs are exposed to these agents, an inflammatory response is triggered and in an effort to resolve injury, this can further exacerbate more physical damage.

Premature infants are deficient in their own CC10 production due to underdevelopment of the lungs and a paucity of cells that normally populate mature and fully developed airways. Individuals diagnosed with COPD also have a deficiency of club cells and the CC10 proteins that they normally produce in the lungs. Many other respiratory conditions also have been associated with a deficiency of native CC10. CC10 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 the CC10 family of proteins referred to as secretoglobins. We have developed two secretoglobins, CC10 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.

Our main candidate for clinical development is the Club Cell 10 kilodalton protein (CC10), also known as Club Cells Secretory Protein (CCSP), CC16, uteroglobin, and secretoglobin 1A1. CC10 is primarily secreted by Club Cells which have historically been called Clara Cells and CCSP positive secreting cells. SCGB3A2 is also referenced in the scientific literature as Uteroglobin Related Protein 1, or UGRP1.

Impact on Lung Inflammation

At least four distinct pathways are affected by CC10:

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.

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.

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. CC10 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.

Impact on Lung Repair

One of the first survival challenges for a premature infant is to breathe on their own, without assistance. The lungs of severely premature infants, born at less than 32 weeks of gestation, do not produce enough lung surfactant in their airways to fully expand, efficiently allow for needed gas exchange and to oxygenate their vital organs. As a result, premature infants often must be intubated and mechanically ventilated, and given lung surfactant therapy, to enable more efficient lung function, oxygen delivery, and survival. This is an invasive process that often results in severe lung inflammation that impairs the normal stages of further lung maturation, leading to development of chronic respiratory morbidity or CRM.

The premature lung lacks the normal surface area, branching and cells needed to assist with expansion, aeration and stability. It is especially susceptible to inflammation because it also does not produce enough CC10, which is important not only in controlling inflammation, but also for the normal development, maintenance, and repair of the cells lining the airways. Translational medicine, using animal models to mimic conditions in premature humans have been instrumental in helping us understand the pathophysiology of immature lung development and subsequent injury. Two different strains of transgenic CC10 knockout mice have helped scientists study the crucial role that the club cells and the protein they produce serve in protecting these small immature airways. Using these special animal models, researchers have reported that a lack of CC10 production in these premature and underdeveloped lungs leads to lower numbers of neuroendocrine cell clusters (NECs) associated with Club Cells. Club Cells are considered to be progenitor cells that give rise to many other types of cells in the lung and are important in development of components of the normal and necessary immune system.

Several other studies also indicate that CC10 and Club Cells are important in development of the respiratory epithelium in infants and serve to help repair the airway epithelium in adults as well.

Both basic science and clinical research have noted that there is a variety of developmental and acquired conditions where a lack of Club Cells and CC10 production can contribute a variety of important medical problems, from the newborn period through adulthood. These deficiencies may be due to under-development of the lungs in the case of premature infants or due to significant scarring and fibrosis of respiratory tissues, resulting in loss of functional airway epithelia, caused by chronic lung disease.