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首頁> 美國衛(wèi)生研究院文獻>Clinical and Translational Science >A Modeling Framework to Characterize Cytokine Release upon T‐Cell–Engaging Bispecific Antibody Treatment: Methodology and Opportunities
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A Modeling Framework to Characterize Cytokine Release upon T‐Cell–Engaging Bispecific Antibody Treatment: Methodology and Opportunities

機譯:表征T細(xì)胞參與雙特異性抗體治療后細(xì)胞因子釋放的建??蚣埽悍椒ê蜋C會

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摘要

T‐cell–engaging bispecific antibodies (T‐BsAbs) are an important class of antibody therapeutics in immuno‐oncology. T‐BsAbs simultaneously bind to 3 on T cells and a tumor‐associated antigen on tumor cells, activate T cells, and redirect T cells’ cytotoxicity against tumor cells. Cytokine release syndrome ( ), a common dose‐limiting adverse event for T‐BsAbs, is associated with T‐cell activation. A “priming” dose strategy (i.e., a lower initial dose followed by a higher maintenance dose) has been implemented in the clinic to mitigate and to achieve efficacious doses with T‐BsAbs. So far, the selection of the optimal priming dosing regimen is largely empirical. A “fit‐for‐purpose” semimechanistic pharmacokinetic/pharmacodynamic model was developed to characterize the cytokine release profiles upon T‐BsAb treatment, including the priming effect observed with repeated dosing. This model can be utilized to simulate cytokine profiles following various dosing regimens and may assist the design of clinical dosing strategies for T‐BsAbs programs.
機譯:參與T細(xì)胞的雙特異性抗體(T-BsAbs)是免疫腫瘤學(xué)中抗體治療的重要類別。 T-BsAbs同時與T細(xì)胞上的3和腫瘤細(xì)胞上的腫瘤相關(guān)抗原結(jié)合,激活T細(xì)胞,并重定向T細(xì)胞對腫瘤細(xì)胞的細(xì)胞毒性。細(xì)胞因子釋放綜合征()是T-BsAb常見的劑量限制性不良事件,與T細(xì)胞活化有關(guān)。臨床上已實施“初始”劑量策略(即,較低的初始劑量后再使用較高的維持劑量),以減輕T-BsAbs并使其達到有效劑量。到目前為止,最佳灌注劑量方案的選擇在很大程度上是憑經(jīng)驗的。開發(fā)了“適合目的”的半力學(xué)藥代動力學(xué)/藥效學(xué)模型,以表征T-BsAb治療后細(xì)胞因子的釋放曲線,包括反復(fù)給藥后觀察到的啟動作用。該模型可用于模擬遵循各種給藥方案的細(xì)胞因子概況,并可能有助于設(shè)計T-BsAbs程序的臨床給藥策略。

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