AT-100 is a novel recombinant human protein rhSP-D – an engineered version of an endogenous protein – that reduces inflammation and infection while modulating the immune response to break the cycle of injury and inflammation.
AT-100 has three critical roles in maintaining healthy lung function:
1. Anti-inflammatory: SP-D has a significant anti-inflammatory function that is independent of its role in pathogen clearance [1-3]. Through a direct interaction with a variety of cell surface receptors, SP-D alters the signal transduction cascade in a variety of immune cell types, resulting in the modulation of inflammatory cytokine production .
2. Immunomodulatory: SP-D is a major component in the innate immune response system in the lung and has been shown to be important in the clearance of bacterial, viral and fungal pathogens [4, 5]. SP-D is known to bind bacteria and fungi, aggregate viruses, and promote opsonization and phagocytosis by macrophages through a variety of receptor-mediated mechanisms [5, 6]. It is also known to be a potent inhibitor of Influenza A virus [7, 8].
3. Lipid Homeostasis: Pulmonary lipids and proteins cover the surface of the lung alveoli, thereby reducing surface tension in the alveoli and keeping breathing effort to a minimum . SP-D is required for the normal structure and function of lung lipids by regulating alveolar surfactant pool sizes and surfactant recycling by the alveolar type II cells [10-12].
- Kishore, U., Greenhough, T. J., Waters, P., Shrive, A. K., Ghai, R., Kamran, M. F., Bernal, A. L., Reid, K. B., Madan, T., Chakraborty, T. (2006). Surfactant proteins SP-A and SP-D: structure, function, and receptors. Mol Immunol, 43(9):1293-1315.
- Wang, J. Y. and Reid, K. B. (2007). The immunoregulatory roles of lung surfactant collectins SP-A, and SP-D, in allergen-induced airway inflammation. Immunobiology, 212(4-5):417-425.
- Haczku, A. (2008). Protective role of the lung collectins surfactant protein A and surfactant protein D in airway inflammation. J Allergy Clin Immunol, 122(5):861-879.
- Kingma, P.S. and J.A. Whitsett. (2006). In defense of the lung: surfactant protein A and surfactant protein D. Curr Opin Pharmacol, 6(3): p. 277-83.
- Wright, J.R. (2005). Immunoregulatory functions of surfactant proteins. Nat Rev Immunol, 5(1): p. 58-68.
- Crouch, E.C., (1998). Structure, biologic properties, and expression of surfactant protein D (SP-D). Biochim Biophys Acta, 1408(2-3): p. 278-89.
- Hillaire, M. L., Haagsman, H. P., Oserhaus, A. D., Rimmelzwaan, G. F., van Eijk, M. (2013). Pulmonary surfactant protein D in first-line innate defense against influenza A virus infections. J Innate Immun, 5(3):197-208.
- Qi, L., Kash, J. C., Dugan, V. G., Jagger, B. W., Lau, Y. F., Sheng, Z. M., Crouch, E. C., Hartshorn, K. L., Taubenberger, J. K. (2011). The ability of pandemic influenza virus hemagglutinins to induce lower respiratory pathology is associated with decreased surfactant protein D binding. Virology, 412(2):426-434.
- Parra, E., Perez-Gil, J. (2015). Composition, structure, and mechanical properties define performance of pulmonary surfactant membranes and films. Chem Phys Lipids, 186:153-175.
- Ikegami, M., et al. (2005). Surfactant protein D influences surfactant ultrastructure and uptake by alveolar type II cells. Am J Physiol Lung Cell Mol Physiol, 288(3): p. L552-61.
- Ikegami, M., et al. (2000). Surfactant metabolism in SP-D gene-targeted mice. Am J Physiol Lung Cell Mol Physiol, 279(3): p. L468-76.
- Korfhagen TR, Sheftelyevich V, Burhans MS, Bruno MD, Ross GF, Wert SE, et al. (1998). Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo. J Biol Chem, 273(43):28438-43.
Airway Therapeutics received Orphan Drug Designation for AT-100 for prevention of BPD in the U.S. and Europe. Research shows the potential for rhSP-D in a range of other inflammatory diseases inside and outside the lung – serving as a pipeline.
- There is no commercialized product available globally for the prevention of BPD.
- Pivotal preclinical studies demonstrate that use of AT-100 in animals treated with commercial lipid therapy prevent the sequelae leading to development of BPD better than that of surfactant therapy alone (current standard of care)
- These data provided the rationale for granting AT-100 the orphan drug designation for prevention of BPD in both the U.S and Europe.
- Favorable feedback from the U.S. FDA & EU regulatory authorities:
- Preclinical program endorsed
- Clinical program endorsed – moving directly to phase II trial with only one randomized phase III study required