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Discovery and Development of AZD1402/PRS-060 a Potent and Selective Blocker of the IL-4 Receptor Alpha
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A1354 - Discovery and Development of AZD1402/PRS-060 a Potent and Selective Blocker of the IL-4 Receptor Alpha
Author Block: G. Matschiner1, A. Allersdorfer1, B. Rattenstetter1, H. Gille2, A. Hohlbaum1, J. Taylor3, D. Keeling3, M. F. Fitzgerald1; 1Pieris Pharmaceuticals, Freising, Germany, 2IASON consulting, Niederzier, Germany, 3IMED RIA, IMED Biotech unit, AstraZeneca, Gothenburg, Sweden.
Rationale: The proinflammatory cytokines IL-4 and IL-13 have been shown to be key players in asthma pathophysiology, both signalling via the IL-4 receptor α subunit. Blocking this receptor interferes with downstream IL-4/IL-13 signalling and dupilumab (Regeneron/Sanofi), an IL-4Rα blocking antibody, has shown efficacy in human asthma clinical trials. Anticalin® proteins are based on human lipocalins and can be engineered to bind specific ligand sites with high potency and selectivity, similar to antibodies. Their simple architecture and small size make Anticalin proteins more robust than antibodies and potentially suitable for inhalation to the lung. We are therefore developing the first inhaled Anticalin protein targeting the IL4-Rα, AZD1402/PRS-060, as a treatment for asthma. Methods and Results: Phage display selection using Pieris’ proprietary Anticalin libraries were used for initial candidate selection and optimisation to identify the Anticalin protein AZD-1402/PRS-060 as a potent (KD 0.023 nM) and selective antagonist of IL-4Rα. In a cell-based functional assay, AZD-1402/PRS-060 demonstrated significantly higher in vitro potency than pitrakinra, an IL-4 mutein that antagonizes IL4-Rα (IC50 0.1 and 8.6 nM, respectively), and comparable in vitro potency to dupilumab. In murine pharmacodynamic models, using IL-13 to induce airway inflammation, AZD-1402/PRS-060 showed effective inhibition of STAT6 regulated target genes (e.g. eotaxin). 2 µg of AZD-1402/PRS-060 showed 86% inhibition of eotaxin expression after 4 hours and inhibition persisted over a 24-hour period. Data in more complex inflammatory models (ovalbumin challenge) also support the potential of AZD-1402/PRS-060 as a future treatment for asthma when given by inhalation. Conclusion: Based on these data and the proven benefit of targeting this receptor, AZD-1402/PRS-060 is progressing into human clinical trials.
Author Block: G. Matschiner1, A. Allersdorfer1, B. Rattenstetter1, H. Gille2, A. Hohlbaum1, J. Taylor3, D. Keeling3, M. F. Fitzgerald1; 1Pieris Pharmaceuticals, Freising, Germany, 2IASON consulting, Niederzier, Germany, 3IMED RIA, IMED Biotech unit, AstraZeneca, Gothenburg, Sweden.
Rationale: The proinflammatory cytokines IL-4 and IL-13 have been shown to be key players in asthma pathophysiology, both signalling via the IL-4 receptor α subunit. Blocking this receptor interferes with downstream IL-4/IL-13 signalling and dupilumab (Regeneron/Sanofi), an IL-4Rα blocking antibody, has shown efficacy in human asthma clinical trials. Anticalin® proteins are based on human lipocalins and can be engineered to bind specific ligand sites with high potency and selectivity, similar to antibodies. Their simple architecture and small size make Anticalin proteins more robust than antibodies and potentially suitable for inhalation to the lung. We are therefore developing the first inhaled Anticalin protein targeting the IL4-Rα, AZD1402/PRS-060, as a treatment for asthma. Methods and Results: Phage display selection using Pieris’ proprietary Anticalin libraries were used for initial candidate selection and optimisation to identify the Anticalin protein AZD-1402/PRS-060 as a potent (KD 0.023 nM) and selective antagonist of IL-4Rα. In a cell-based functional assay, AZD-1402/PRS-060 demonstrated significantly higher in vitro potency than pitrakinra, an IL-4 mutein that antagonizes IL4-Rα (IC50 0.1 and 8.6 nM, respectively), and comparable in vitro potency to dupilumab. In murine pharmacodynamic models, using IL-13 to induce airway inflammation, AZD-1402/PRS-060 showed effective inhibition of STAT6 regulated target genes (e.g. eotaxin). 2 µg of AZD-1402/PRS-060 showed 86% inhibition of eotaxin expression after 4 hours and inhibition persisted over a 24-hour period. Data in more complex inflammatory models (ovalbumin challenge) also support the potential of AZD-1402/PRS-060 as a future treatment for asthma when given by inhalation. Conclusion: Based on these data and the proven benefit of targeting this receptor, AZD-1402/PRS-060 is progressing into human clinical trials.
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