Recombinant human CC10 protein for treatment and prevention of chronic lung allograft dysfunction

Abstract Over 5,000 lung transplants (LTx) are performed in the US each year to save the lives of patients in respiratory failure due to COPD, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and other terminal lung conditions. The vast majority of LTx, long-term survival is significantly limited by chronic lung allograft dysfunction (CLAD) with a median survival of 6 years post-transplant. New therapies are urgently needed to improve clinical outcomes in LTx and CLAD. Native CC10/SCGB1A1 is an important host defense, immunomodulatory, and homeostatic protein in the lungs, which is known to be deficient in CLAD. Recombinant human CC10 protein (rhCC10) can augment native CC10 levels in vivo and is a biologic candidate potentially to treat and prevent CLAD. It has shown efficacy in decreasing lung histopathology in a murine models of; 1) orthotopic lung transplant model of CLAD, 2) bronchiolitis obliterans caused by orthotopic bone marrow transplant, in addition to reducing pulmonary inflammation and fibrosis in several other animal models of acute lung injury and pulmonary fibrosis. RhCC10 was also shown to be safe in 3 human studies and showed potent anti-inflammatory effects in the lungs of severely premature infants experiencing respiratory distress. In CLAD patients, the optimal route of administration is by inhalation, however, inhalation is an inherently inefficient delivery method. Up to 70% of each drug dose may be wasted, therefore, it is advantageous to optimize drug potency to enable production and delivery of sufficient quantities to impact clinical endpoints. Our group has developed methods to enhance the potency of rhCC10 and the proposed studies will scale-up these methods, characterize the resulting products, and optimize them for maximal anti-inflammatory activity to lay groundwork for in vivo studies of preparations with enhanced potency.