Therapeutic neutralization of Oncostatin M (OSM) causes mechanism‐driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of doses (and dosing intervals) that optimize efficacy and safety. We utilized clinical data from studies of an anti‐OSM monoclonal antibody (GSK2330811) in healthy volunteers (n = 49) and systemic sclerosis patients (n = 35), to quantitatively determine the link between OSM and alterations in red blood cell (RBC) and platelet production. Longitudinal changes in hematopoietic variables (including RBCs, reticulocytes, platelets, erythropoietin, and thrombopoietin) were linked in a physiology‐based model, to capture the long‐term effects and variability of therapeutic OSM neutralization on human hematopoiesis. Free serum OSM stimulated precursor cell production through sigmoidal relations, with higher maximum suppression (Imax) and OSM concentration for 50% suppression (IC50) for platelets (89.1% [95% confidence interval: 83.4–93.0], 6.03 pg/mL [4.41–8.26]) than RBCs (57.0% [49.7–64.0], 2.93 pg/mL [2.55–3.36]). Reduction in hemoglobin and platelets increased erythro‐ and thrombopoietin, respectively, prompting reticulocytosis and (partially) alleviating OSM‐restricted hematopoiesis. The physiology‐based model was substantiated by preclinical data and utilized in exploration of once‐weekly or every other week dosing regimens. Predictions revealed an (for the indication) unacceptable occurrence of grade 2 (67% [58–76], 29% [20–38]) and grade 3 (17% [10–25], 3% [0–7]) anemias, with limited thrombocytopenia. Individual extent of RBC precursor modulation was moderately correlated to skin mRNA gene expression changes. The physiological basis and consideration of interplay among hematopoietic variables makes the model generalizable to other drug and nondrug scenarios, with adaptations for patient populations, diseases, and therapeutics that modulate hematopoiesis or exhibit risk of anemia and/or thrombocytopenia.

中文翻译：

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预测制瘤素 M 治疗中和对人类造血的长期影响

制瘤素 M (OSM) 的治疗中和会导致机制驱动的贫血和血小板减少症，从而缩小治疗窗，使优化疗效和安全性的剂量（和给药间隔）选择变得复杂。我们利用了健康志愿者中抗 OSM 单克隆抗体 (GSK2330811) 研究的临床数据（n= 49）和系统性硬化症患者（n= 35)，定量确定 OSM 与红细胞 (RBC) 和血小板生成变化之间的联系。将造血变量（包括红细胞、网织红细胞、血小板、促红细胞生成素和血小板生成素）的纵向变化与基于生理学的模型联系起来，以捕获治疗性 OSM 中和对人类造血的长期影响和变异性。游离血清 OSM 通过 S 形关系刺激前体细胞产生，具有更高的最大抑制（I最大限度）和 50% 抑制的 OSM 浓度（IC50) 血小板 (89.1% [95% 置信区间: 83.4–93.0], 6.03 pg/mL [4.41–8.26]) 高于红细胞 (57.0% [49.7–64.0], 2.93 pg/mL [2.55–3.36])。血红蛋白和血小板的减少分别增加红细胞和血小板生成素，促进网织红细胞增多并（部分）缓解 OSM 限制的造血作用。基于生理学的模型得到了临床前数据的证实，并用于探索每周一次或每隔一周的给药方案。预测显示（针对该适应症）2 级（67% [58–76]、29% [20–38]）和 3 级（17% [10–25]、3% [0–7]）的发生率不可接受贫血，伴有有限的血小板减少症。红细胞前体调节的个体程度与皮肤 mRNA 基因表达变化适度相关。生理学基础和造血变量之间相互作用的考虑使该模型可推广到其他药物和非药物场景，并适应患者群体、疾病和调节造血或表现出贫血和/或血小板减少症风险的治疗方法。