We established the iMod.Fc program to leverage our knowledge of the Resokine pathway to vary exposure and activity of the iMod domain through protein engineering. The goal of the program was to develop a potential therapeutic which would possess only the N-terminal immuno-modulatory activities of Resokine and fuse it to the FC region of a human antibody.
Our Fc fusion experiments helped delineate how to increase the serum half-life and enhance the exposure of the iMod domain of Resokine while maintaining activity and provide insights into this domain harboring immuno-modulatory activity. Experiments have indicated that Fc fusion proteins can be generated which increase exposure and maintain iMod domain activity.
Key Research Finding: Identification of Receptor for ATYR1923
The Company has identified Neuropilin-2 (NRP-2) as a binding partner for ATYR1923 from a screen of greater than 4,500 human membrane proteins. NRP-2 is a pleiotropic receptor that can bind to a number of different ligands. It has a well-established role in the development of the neural and lymphatic systems and an emerging role in the adult immune system. aTyr is currently evaluating the role of NRP-2 interactions in the control of immune responses, and designing optimal therapeutic approaches to modulate this newly-discovered receptor in the Resokine pathway. The Company believes the discovery of this receptor will aid in the clinical development of the ATYR1923 program.
Interstitial Lung Diseases (ILDs) and the Role of Immunology
ILD develops in approximately 85% of Jo-1 positive anti-synthetase patients with antibodies to Resokine. It can include the presence of focal immune cell infiltrates and an acinar pattern of involvement on chest computed tomography (CT) scan, lymphocytic predominance on broncho-alveolar lavage and lymphocytic invasion of alveolar and interstitial lung tissues on biopsy, and can advance to fibrosis. The pathological patterns in Jo-1 antibody ILD include cellular and fibrotic forms of non-specific interstitial pneumonitis, usual interstitial pneumonitis and diffuse alveolar damage. The development of ILD in Jo-1 antibody patients, particularly the acute severe forms of the disease, portends high morbidity and mortality. Elevations in a number of circulating immune proteins are observed in Jo-1 antibody associated ILD including interferon (IFN)-inducible chemokines CXCL9, or MIG, and CXCL10 or IP-10, IL-8 and IL-6.
Among the various forms of ILD, we have identified several that result in severe and progressive lung disease and share immune-pathophysiology features that have the potential to be impacted by our demonstrated ATYR1923 preclinical activities. Examples of pulmonary diseases with an immune component include idiopathic interstitial pneumonias, sarcoidosis, chronic hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, and ILD in the setting of systemic sclerosis or rheumatoid arthritis.
Clinical Development Plan
aTyr Pharma is conducting a Phase 1 clinical program for the ATYR1923. This randomized, double-blind, placebo-controlled study will investigate the safety, tolerability, immunogenicity, and pharmacokinetics of intravenous ATYR1923 in healthy volunteers.
Please click here to learn more about our ongoing clinical programs: Clinical Trials