Bansal Loveleena, Nichols Eva-Maria, Howsmon Daniel P, Neisen Jessica, Bessant Christina M, Cunningham Fraser, Petit-Frere Sebastien, Ludbrook Steve, Damian Valeriu
Systems Modeling and Translational Biology, Computational Sciences, GSK, Upper Providence, Collegeville, PA, United States.
Immunology Research Unit, GSK, Stevenage, United Kingdom.
Front Pharmacol. 2022 Apr 19;13:855743. doi: 10.3389/fphar.2022.855743. eCollection 2022.
The complement pathway plays a critical role in innate immune defense against infections. Dysregulation between activation and regulation of the complement pathway is widely known to contribute to several diseases. Nevertheless, very few drugs that target complement proteins have made it to the final regulatory approval because of factors such as high concentrations and dosing requirements for complement proteins and serious side effects from complement inhibition. A quantitative systems pharmacology (QSP) model of the complement pathway has been developed to evaluate potential drug targets to inhibit complement activation in autoimmune diseases. The model describes complement activation the alternative and terminal pathways as well as the dynamics of several regulatory proteins. The QSP model has been used to evaluate the effect of inhibiting complement targets on reducing pathway activation caused by deficiency in factor H and CD59. The model also informed the feasibility of developing small-molecule or large-molecule antibody drugs by predicting the drug dosing and affinity requirements for potential complement targets. Inhibition of several complement proteins was predicted to lead to a significant reduction in complement activation and cell lysis. The complement proteins that are present in very high concentrations or have high turnover rates (C3, factor B, factor D, and C6) were predicted to be challenging to engage with feasible doses of large-molecule antibody compounds (≤20 mg/kg). Alternatively, complement fragments that have a short half-life (C3b, C3bB, and C3bBb) were predicted to be challenging or infeasible to engage with small-molecule compounds because of high drug affinity requirements (>1 nM) for the inhibition of downstream processes. The drug affinity requirements for disease severity reduction were predicted to differ more than one to two orders of magnitude than affinities needed for the conventional 90% target engagement (TE) for several proteins. Thus, the QSP model analyses indicate the importance for accounting for TE requirements for achieving reduction in disease severity endpoints during the lead optimization stage.
补体途径在针对感染的固有免疫防御中发挥着关键作用。众所周知，补体途径激活与调节之间的失调会导致多种疾病。然而，由于补体蛋白所需的高浓度和给药要求以及补体抑制带来的严重副作用等因素，很少有针对补体蛋白的药物最终获得监管批准。已开发出一种补体途径的定量系统药理学（QSP）模型，以评估在自身免疫性疾病中抑制补体激活的潜在药物靶点。该模型描述了补体激活的替代途径和终末途径以及几种调节蛋白的动态变化。QSP模型已用于评估抑制补体靶点对减少因因子H和CD59缺乏引起的途径激活的影响。该模型还通过预测潜在补体靶点的药物给药和亲和力要求，为开发小分子或大分子抗体药物的可行性提供了参考。预测抑制几种补体蛋白会导致补体激活和细胞裂解显著减少。预计浓度非常高或周转率高的补体蛋白（C3、因子B、因子D和C6），要以可行剂量的大分子抗体化合物（≤20mg/kg）与之结合具有挑战性。另外，由于抑制下游过程对药物亲和力要求较高（>1nM），预计半衰期短的补体片段（C3b、C3bB和C3bBb）与小分子化合物结合具有挑战性或不可行。预测降低疾病严重程度所需的药物亲和力要求与几种蛋白质传统90%靶点占有率（TE）所需的亲和力相差一个到两个以上数量级。因此，QSP模型分析表明在先导化合物优化阶段考虑实现疾病严重程度终点降低所需的TE要求非常重要。
