Safety, Pharmacokinetics, and Anti-inflammatory Effects of Intratracheal Recombinant Human Clara Cell Protein in Premature Infants with Respiratory Distress Syndrome

Abstract

Clara cell 10-kD protein (CC10) is a potent anti-inflammatory protein that is normally abundant in the respiratory tract. CC10 is deficient and oxidized in premature infants with poor clinical outcome (death or the development of bronchopulmonary dysplasia). The safety, pharmacokinetics, and anti-inflammatory activity of recombinant human CC10 (rhCC10) were evaluated in a randomized, placebo-controlled, doubleblinded, multicenter trial in premature infants with respiratory distress syndrome. A total of 22 infants (mean birth weight: 932 g; gestational age: 26.9 wk) received one intratracheal dose of placebo (n ϭ 7) or 1.5 mg/kg (n ϭ 8) or 5 mg/kg (n ϭ 7) rhCC10 within 4 h of surfactant treatment. Pharmacokinetic analyses demonstrated that the serum halflife was 11.6 (1.5 mg/kg group) and 9.9 h (5 mg/kg group). Excess circulating CC10 was eliminated via the urine within 48 h. rhCC10-treated infants showed significant reductions in total cell count (p Ͻ 0.0002), neutrophil counts (p Ͻ 0.001), and total protein concentrations (p Ͻ 0.01) and tended to have decreased IL-6 (p Ͻ 0.07) in tracheal aspirate fluid collected over the first 3 d of life. Infants in all three groups showed comparable growth. At 36 wk postmenstrual age, five of seven infants were still hospitalized and two of seven infants were receiving oxygen in the placebo group compared with two of seven hospitalized and one of seven receiving oxygen in the 1.5-mg/kg group and four of six hospitalized and three of six receiving oxygen in the 5-mg/kg group. A single intratracheal dose of rhCC10 was well tolerated and had significant anti-inflammatory effects in the lung. Multiple doses of rhCC10 will be investigated for efficacy in reducing pulmonary inflammation and ameliorating bronchopulmonary dysplasia in future studies. Bronchopulmonary dysplasia (BPD) affects 20 -60% of all premature, very low birth weight infants. It is associated with substantial morbidity and mortality as well as extremely high health care costs. Although the widespread use of exogenous surfactant and antenatal steroid therapy has reduced the overall severity of BPD, the prevalence of this condition has increased with improved survival of very low birth weight infants. BPD is a multifactorial disease process that is the end result of an immature, surfactant-deficient lung that has been exposed to hyperoxia, mechanical ventilation, and infection. These forces initiate a cascade of proinflammatory cytokines that lead to the development of significant inflammatory changes and chronic lung injury.Clara cell 10-kD protein (CC10) is also known as uteroglobin. It is a small homodimeric secretory protein that is produced by mucosal epithelial cells (1). In humans, Clara cells are the main site of CC10 production (located in the airways), and several other organs synthesize smaller amounts of mRNA encoding this protein (2-4). CC10 also circulates in the blood

Comparable effect of conventional ventilation versus early high-frequency oscillation on serum CC16 and IL-6 levels in preterm neonates

“…Such measurements could offer important insights into the effect of ventilation modes on these proteins at the lung level, possibly justifying novel therapeutic agents, such as the intratracheal administration of recombinant human Clara cell protein. 35 Finally, other biomarkers, which may be more appropriate for the evaluation of lung injury, should be examined, especially in association with multiple cytokine interactions.…”

Prevention and treatment of bronchopulmonary dysplasia: current status and future prospects

“…In a small randomized trial, two different dose regimens of a single intratracheal dose of recombinant human CC10 in ventilated infants less than 1300 grams were compared to placebo. 52 The study drug was well tolerated and led to a significant reduction of tracheal aspirate neutrophil counts and protein concentrations as markers of pulmonary inflammation and damage to the alveolar-capillary integrity during the first 3 days of life. The trial was not powered to show any effect on BPD.…”

Advances in emerging treatment options to prevent bronchopulmonary dysplasia

“…CCSP concentrations have been demonstrated to correlate negatively with the concentration of inspired oxygen required by preterm infants with RDS [64]. In a prospective study, CCSP levels in tracheal aspirates were lower from day one after birth in infants who developed BPD compared to those who did not [65].…”

“…In 22 infants with birth weights between 700 and 1300 gms, there was no statistically significant reduction in BPD (RR 0.50, 95% CI 0.06 to 4.33) [64]. A Cochrane review identified only one pilot study [66].…”