Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy (M.M., Y.C.) and Lineberger Comprehensive Cancer Center, School of Medicine (Y.C.), University of North Carolina at Chapel Hill, North Carolina; Department of Biochemistry (J.M.), University of Belgrade, Faculty of Chemistry, Belgrade, Serbia; and Clinical Pharmacology and Pharmacometrics, Janssen Research & Development (W.W.), LLC, Spring House, Pennsylvania.
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy (M.M., Y.C.) and Lineberger Comprehensive Cancer Center, School of Medicine (Y.C.), University of North Carolina at Chapel Hill, North Carolina; Department of Biochemistry (J.M.), University of Belgrade, Faculty of Chemistry, Belgrade, Serbia; and Clinical Pharmacology and Pharmacometrics, Janssen Research & Development (W.W.), LLC, Spring House, Pennsylvania
Mol Pharmacol. 2023 Dec 15;105(1):1-13. doi: 10.1124/molpharm.123.000726.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid- (A) protein accumulation in the brain. Passive immunotherapies using monoclonal antibodies for targeting A have shown promise for AD treatment. Indeed, recent US Food and Drug Administration approval of aducanumab and lecanemab, alongside positive donanemab Phase III results demonstrated clinical efficacy after decades of failed clinical trials for AD. However, the pharmacological basis distinguishing clinically effective from ineffective therapies remains unclear, impeding development of potent therapeutics. This study aimed to provide a quantitative perspective for effectively targeting A with antibodies. We first reviewed the contradicting results associated with the amyloid hypothesis and the pharmacological basis of A immunotherapy. Subsequently, we developed a quantitative systems pharmacology (QSP) model that describes the non-linear progression of A pathology and the pharmacologic actions of the A-targeting antibodies. Using the QSP model, we analyzed various scenarios for effective passive immunotherapy for AD. The model revealed that binding exclusively to the A monomer has minimal effect on A aggregation and plaque reduction, making the antibody affinity toward A monomer unwanted, as it could become a distractive mechanism for plaque reduction. Neither early intervention, high brain penetration, nor increased dose could yield significant improvement of clinical efficacy for antibodies targeting solely monomers. Antibodies that bind all A species but lack effector function exhibited moderate effects in plaque reduction. Our model highlights the importance of binding aggregate A species and incorporating effector functions for efficient and early plaque reduction, guiding the development of more effective therapies for this devastating disease. SIGNIFICANCE STATEMENT: Despite previous unsuccessful attempts spanning several decades, passive immunotherapies utilizing monoclonal antibodies for targeting amyloid-beta (A) have demonstrated promise with two recent FDA approvals. However, the pharmacological basis that differentiates clinically effective therapies from ineffective ones remains elusive. Our study offers a quantitative systems pharmacology perspective, emphasizing the significance of selectively targeting specific A species and importance of antibody effector functions. This perspective sheds light on the development of more effective therapies for this devastating disease.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是大脑中淀粉样蛋白（A）的积累。使用针对 A 的单克隆抗体的被动免疫疗法已显示出治疗 AD 的前景。事实上，最近美国食品和药物管理局批准了 aducanumab 和 lecanemab，以及积极的 donanemab III 期结果表明，经过几十年的 AD 临床试验失败后，具有临床疗效。然而，区分临床有效和无效治疗的药理学基础仍不清楚，这阻碍了有效治疗方法的开发。本研究旨在为抗体有效靶向 A 提供定量视角。我们首先回顾了与淀粉样蛋白假说和 A 免疫疗法的药理学基础相关的矛盾结果。随后，我们开发了一个定量系统药理学（QSP）模型，该模型描述了 A 病理的非线性进展和针对 A 的抗体的药理作用。使用 QSP 模型，我们分析了 AD 有效被动免疫治疗的各种情况。该模型表明，仅与 A 单体结合对 A 聚集和斑块减少几乎没有影响，使抗体对 A 单体的亲和力变得不必要，因为它可能成为减少斑块的一种干扰机制。仅针对单体的抗体的早期干预、高脑穿透性或增加剂量都不能显著改善临床疗效。与所有 A 物种结合但缺乏效应功能的抗体在斑块减少方面表现出适度的效果。我们的模型强调了结合聚集 A 物种和纳入效应功能的重要性，以实现有效的早期斑块减少，为这种毁灭性疾病的更有效治疗方法的开发提供了指导。意义声明：尽管过去几十年的尝试都不成功，但利用单克隆抗体靶向淀粉样蛋白-β（A）的被动免疫疗法已显示出两种最近 FDA 批准的有希望的结果。然而，区分临床有效治疗方法和无效治疗方法的药理学基础仍然难以捉摸。我们的研究提供了一个定量系统药理学的视角，强调了有针对性地选择特定 A 物种的重要性和抗体效应功能的重要性。这一观点为这种毁灭性疾病的更有效治疗方法的开发提供了启示。
