Inhaled calcium salts inhibit tobacco smoke-induced inflammation by modulating expression of chemokines and cytokines.

Tobacco smoke-induced lung inflammation in patients with chronic obstructive pulmonary disease (COPD) worsens with disease progression and acute exacerbations caused by respiratory infections. Chronic therapies to manage COPD center on bronchodilators to improve lung function and inhaled corticosteroids (ICS) to help reduce the risk of exacerbations. Novel therapies are needed that reduce the underlying inflammation associated with COPD and the inflammation resulting from respiratory infections that worsen disease. The lung is lined with airway surface liquid (ASL), a rheologically active material that provides an innate defense for the airway against inhaled particulate and is continuously cleared from the airways by mucociliary clearance. The rheological properties of the ASL can be altered by changes in airway hydration and by cations, such as calcium, that interact with electronegative glycoproteins. The effect of inhaled salts on inflammation resulting from tobacco smoke exposure was studied to determine if cations could be used to alter the properties of the ASL and reduce inflammation. Inhaled calcium salts, but not sodium or magnesium salts, reduced cellular inflammation and key chemokines and cytokines that were induced by tobacco smoke exposure. Similar anti-inflammatory effects of calcium salts were observed using in vitro cultures of human monocyte derived macrophages and human bronchial epithelial cells. The data suggest that inhaled calcium salts may act broadly on both biophysical and biological pathways to reduce pulmonary inflammation.

A mouse model for evaluation of efficacy and concomitant toxicity of anti-human CXCR4 therapeutics.

The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with "surrogate" anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development. Therefore, mouse models that allow concomitant evaluation of drug efficacy and safety are highly desirable. The C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for tumor-targeted and immuno-oncology therapeutics, with multiple mouse immunization-derived antibodies undergoing clinical trials. Given the pleiotropic role of CXCR4 in cancer biology, we anticipate continuous interest in this target, particularly in the testing of therapeutic combinations for immuno-oncology. Here, we describe the generation and validation of the first mouse knock-in of the whole coding region of human CXCR4. Homozygous human CXCR4 knock-in (hereafter designated as HuCXCR4KI) mice were viable and outwardly healthy, reproduced normally and nursed their young. The expression pattern of human CXCR4 in this model was similar to that of CXCR4 expression in normal human tissues. The human CXCR4 knock-in gene was expressed as a biologically active protein, thereby allowing normal animal development and adequate"homing" of leukocytes to the bone marrow. To further validate our model, we used an in vivo functional assay of leukocyte mobilization from bone marrow to peripheral blood by blocking CXCR4 signaling. Both an anti-human CXCR4 -specific blocking antibody and the small molecule CXCR4 inhibitor AMD3100 induced increased leukocyte counts in peripheral blood, whereas an anti-mouse CXCR4 -specific blocking antibody had no effect. This new mouse model is useful to evaluate efficacy and safety of anti-human CXCR4 -specific drugs as single agents or in combination therapies, particularly in the oncology, immuno-oncology, wound healing and chronic inflammation therapeutic areas.