A long-acting high affinity anti-TSLP antibody (GB-0895) for severe asthma identified leveraging a proprietary machine learning platform

哮喘 计算机科学 抗体 医学 免疫学
作者
Tanvi Gawde,Kapil Mayawala,Antonios O. Aliprantis,Jaileene Hernandez Escalante,Hongwei Han,Sumana Ullas,Ming Bai,Charles Sinclair,Wojciech Dworakowski,Lovely Goyal,Khaled M. A. Amiri,Andrew Robertson,Stephanie Straley,Kristen Hopson,Adam Root,Luisa Salter–Cid,Lana Dinic,Victoria Szenes,Alexandra Snyder,Heather Van Epps
标识
DOI:10.1183/13993003.congress-2024.pa2983
摘要

Background: Inhibition of Thymic Stromal Lymphopoietin (TSLP) is a safe and effective mechanism to treat severe asthma, irrespective of endotype. The approved anti-TSLP antibody (tezepelumab) requires monthly administration; a longer duration treatment could improve adherence and outcomes. Aims: To develop and characterize a novel long-acting anti-TSLP antibody. Methods and results: Translational systems pharmacology modeling was used to predict the half-life and affinity targets, relative to tezepelumab, to support a longer-acting subcutaneous dosing regimen for a next generation anti-TSLP antibody. We leveraged a proprietary machine learning platform to help identify monoclonal antibody PRO-17101 that exceeded the affinity target, binding human TSLP with an affinity of 106 fM, a 20-fold improvement over the benchmark. Mutations were introduced into the Fc region of PRO-17101 to extend half-life to create GB-0895. PRO-17101 and/or GB-0895 were active in multiple cell-based TSLP stimulation assays with potencies generally exceeding the benchmark. In mouse models of allergic airway inflammation, PRO-17101 neutralized TSLP and reduced leukocytes, eosinophils and IgE in the bronchoalveolar lavage along with serum IgE and Th2 mediators. Binding of GB-0895 was specific for TSLP in a screen against over 6000 extracellular human proteins. In a cynomolgus monkey study, GB-0895 was well tolerated and displayed a pharmacokinetic profile predicted to fulfill the targeted dosing regimen. Conclusions: GB-0895 has the potential for best-in-class dosing for patients with severe asthma. A phase 1 dose escalation trial in asthma patients is underway.

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