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1型人类免疫缺陷病毒预防单克隆抗体早期临床试验中的剂量探索

Dose finding in early-phase human immunodeficiency virus type 1 prevention monoclonal antibody clinical trials.

作者信息

Huang Yunda, Zhang Bo, Zhang Lily, Mayer Bryan T, Martin Troy, Hahn William, Hyrien Ollivier, Gelderblom Huub C

机构信息

Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Department of Global Health, University of Washington, Seattle, WA, USA.

出版信息

Clin Trials. 2025 Aug;22(4):442-451. doi: 10.1177/17407745251347280. Epub 2025 Jul 5.

Abstract

Human immunodeficiency virus type 1 remains a major public health burden with 39 million people living with human immunodeficiency virus type 1 and 1.3 million new diagnoses in 2023, despite the recent approval of multiple antiretroviral-based prevention products. While the development of a safe and effective human immunodeficiency virus type 1 vaccine remains the ultimate goal for controlling the worldwide pandemic, progress has been hindered by unprecedented challenges, including the extraordinary genetic diversity of human immunodeficiency virus type 1, the inability of current vaccines to induce broadly reactive antibody responses, and the lack of clear immune correlates of protection to serve as benchmarks for vaccine development. Passive administration of broadly neutralizing monoclonal antibodies that are engineered versions of naturally occurring antibodies has emerged as a potential complement to current human immunodeficiency virus type 1 prevention modalities. These antibodies are isolated from people with human immunodeficiency virus type 1 and can neutralize a broad range of human immunodeficiency virus type 1 viruses. Importantly, advances in antibody engineering have improved the pharmacokinetics of these monoclonal antibodies, offering potential for lower levels and/or less frequent monoclonal antibody dosing with greater feasibility and accessibility for human immunodeficiency virus type 1 prevention. Evaluating monoclonal antibody candidates in human immunodeficiency virus type 1 prevention trials, dose-finding and optimization requires a careful balance between virus-neutralization coverage, cost considerations, and practical constraints. To achieve this, pharmacokinetic modeling of antibody concentrations over time, combined with pharmacodynamics modeling of the relationship between neuralization titers and prevention efficacy, serves as a core of the statistical framework. In addition, for human immunodeficiency virus type 1 monoclonal antibodies administered to individuals without human immunodeficiency virus type, neutralization titers can be reliably predicted from antibody concentrations, owning to the preservation of neutralization function post-administration of these monoclonal antibodies. Within this framework, the antibody-mediated prevention efficacy trials of VRC01, an human immunodeficiency virus type 1 monoclonal antibody, and a meta-analysis of 16 different monoclonal antibodies in non-human primates provided consistent evidence that neutralization titer is a potential pharmacodynamics biomarker of monoclonal antibody prevention efficacy. These findings support the use of integrated pharmacokinetics/pharmacodynamics modeling as a foundation for dose finding of human immunodeficiency virus type 1 monoclonal antibodies. However, in the context of combination monoclonal antibody regimens, additional challenges arise. The total dose cost, operational feasibility, and the influence of dosing ratios on neutralization breadth and potency across diverse human immunodeficiency virus type 1 viral strains are important areas for further research. While monoclonal antibody clinical trials share some common design features with therapeutic small molecule drug trials, monoclonal antibodies possess unique safety, pharmacokinetics and pharmacodynamics profiles that require dedicated statistical and clinical considerations, particularly when used for prevention of viral infections. In this article, we highlight dose-finding efforts particularly for combination monoclonal antibodies regimens, including the selection of optimal dosing ratio and total dose amount in the context of human immunodeficiency virus type 1 prevention. Looking ahead, future directions in monoclonal antibody-based human immunodeficiency virus type 1 prevention include efforts to enhance dose-associated cost-effectiveness, and the identification and validation of robust pharmacokinetic and pharmacodynamic markers that are predictive of the prevention efficacy of combination monoclonal antibodies.

摘要

尽管最近多款基于抗逆转录病毒的预防产品已获批上市,但人类免疫缺陷病毒1型(HIV-1)仍是一项重大的公共卫生负担,2023年有3900万人感染HIV-1,新增诊断病例达130万例。虽然开发一种安全有效的HIV-1疫苗仍是控制全球大流行的最终目标,但进展受到了前所未有的挑战阻碍,包括HIV-1的非凡基因多样性、现有疫苗无法诱导广泛反应性抗体反应,以及缺乏明确的保护性免疫相关指标作为疫苗开发的基准。被动给予经工程改造的天然存在抗体的广泛中和单克隆抗体已成为当前HIV-1预防模式的潜在补充。这些抗体从HIV-1感染者中分离出来,可中和多种HIV-1病毒。重要的是,抗体工程的进展改善了这些单克隆抗体的药代动力学,为降低单克隆抗体剂量水平和/或减少给药频率提供了可能,使其在HIV-1预防方面更具可行性和可及性。在HIV-1预防试验中评估单克隆抗体候选药物、确定剂量和进行优化,需要在病毒中和覆盖率、成本考量和实际限制之间仔细权衡。为此,随时间变化的抗体浓度药代动力学建模,结合中和效价与预防效果之间关系的药效动力学建模,构成了统计框架的核心。此外,对于给予未感染HIV-1个体的HIV-1单克隆抗体,由于这些单克隆抗体给药后中和功能得以保留,中和效价可从抗体浓度可靠预测。在此框架内,HIV-1单克隆抗体VRC01的抗体介导预防效果试验,以及对16种不同单克隆抗体在非人灵长类动物中的荟萃分析,提供了一致证据,表明中和效价是单克隆抗体预防效果的潜在药效学生物标志物。这些发现支持将综合药代动力学/药效动力学建模作为HIV-1单克隆抗体剂量确定的基础。然而,在联合单克隆抗体方案的背景下,会出现其他挑战。总剂量成本、操作可行性,以及给药比例对不同HIV-1病毒株中和广度和效力的影响,是需要进一步研究的重要领域。虽然单克隆抗体临床试验与治疗性小分子药物试验有一些共同的设计特点,但单克隆抗体具有独特的安全性、药代动力学和药效学特征,需要专门的统计和临床考量,尤其是用于预防病毒感染时。在本文中,我们重点介绍了特别是联合单克隆抗体方案的剂量确定工作,包括在HIV-1预防背景下选择最佳给药比例和总剂量。展望未来,基于单克隆抗体的HIV-1预防的未来方向包括努力提高剂量相关的成本效益,以及识别和验证可预测联合单克隆抗体预防效果的可靠药代动力学和药效学标志物。

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