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A1064 - Pre-Clinical Characterization of iMod.Fc, an Immune-Modulatory Therapeutic with Potentially Broad Application in Interstitial Lung Diseases
Author Block: K. Ogilvie, Q. Xu, M. T. Do, R. A. Adams, D. Lee, M. Thomas, L. Nangle, A. Cubitt, D. King, J. D. Mendlein; aTyr Pharma, San Diego, CA, United States.
Introduction: During the evolution of complex organisms, aminoacyl-tRNA synthetase genes (AARS) evolved to incorporate new sequences and generate multiple splice variants which lose their tRNA synthetase activity and take on novel functions (Lo et al., Science, 2014). Histidyl-tRNA synthetase and its splice variants are secreted and exhibit extracellular activity, which we have termed the Resokine pathway. Based on the overexpression in the lung of a splice variant (SV9) encoding the N-terminal domain of Resokine, we hypothesized that it modulates the activity of immune cells in interstitial lung diseases (ILDs) and consequently ameliorates disease.
Rationale: In previous work, we showed that administration of Resokine proteins containing the N-terminal immunomodulatory (iMod) domain reduced bleomycin-induced lung fibrosis in mice, demonstrating the functional significance of the Resokine pathway in the lung. Based on these observations, we sought to engineer and characterize a clinical candidate with appropriate pharmaceutical properties for clinical study in ILD. Specifically, we sought to extend the duration of action of the iMod by fusion to human IgG1 Fc.
Methods: iMod.Fc, a Resokine N-terminal domain fused to human Fc, was expressed in E. coli and purified to homogeneity, confirming low endotoxin (LAL assay) and pathogen-associated molecular patterns (PAMPs) signals by a novel cell-based method. A rat model of bleomycin-induced lung fibrosis was employed to explore the effects of iMod.Fc in vivo, including whole body plethysmography and histological disease scoring on Day 21. PK studies and GLP-compliant one- and three- month toxicology studies were conducted in rats and non-human primates (NHPs).
Results: The Resokine iMod domain Fc fusion protein exhibited the therapeutic potential of the iMod domain while having a long in vivo half-life. iMod.Fc had a terminal half-life of ~ 3 days in rats and ~ 4.5 days in NHPs, in contrast to the isolated iMod domain that had a terminal half-life of ~ 20 minutes in rats. In rat bleomycin-induced lung fibrosis, iMod.Fc at 0.1-3 mg/kg weekly beginning on Day 9 exerted therapeutic activity as revealed by reversal of bleomycin-induced changes in respiratory parameters and decreased histological fibrosis (Ashcroft score) and immune infiltration. One- and three- month GLP-compliant studies found no adverse test-article related findings. The no observed adverse effect level (NOAEL) was 60 mg/kg in both species.
Conclusion: iMod.Fc has been engineered to have a long duration of action and is efficacious in bleomycin-induced lung fibrosis pre-clinical models when administered weekly. Based on the pre-clinical data, clinical testing is planned.