Chugai Pharmaceutical Co., Ltd., Yokohama 244-8602, Japan.
Chugai Pharmabody Research Pte., Ltd., Singapore 138623, Singapore.
Int J Mol Sci. 2024 Oct 30;25(21):11679. doi: 10.3390/ijms252111679.
The advent of recycling antibodies, leveraging pH-dependent antigen binding and optimized FcRn interaction, has advanced the field of antibody therapies, enabling extended durability and reduced dosages. Eculizumab (Soliris) demonstrated the efficacy of C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH), while its derivative, ravulizumab (Ultomiris), recognized as a recycling antibody, extended the dosing intervals. However, limitations including intravenous administration and inefficacy in patients with the R885H single-nucleotide polymorphism (SNP) in C5 could necessitate alternative solutions. Crovalimab (PiaSky), a next-generation recycling antibody, overcomes these challenges with innovative charge engineering, achieving the enhanced cellular uptake of C5-crovalimab complexes and targeting a unique C5 epitope, allowing for efficacy regardless of the R885H SNP. This study highlights crovalimab's distinctive molecular features, showing its eliminated binding to Fcγ receptors and C1q, alongside its optimized antigen binding characteristics. The impact of charge engineering was reconfirmed in mice, demonstrating faster C5 clearance than recycling antibodies. Notably, in the maintenance dosing regimen, crovalimab neutralizes approximately seven C5 molecules per antibody on average. Furthermore, its design also reduces the viscosity to facilitate high-concentration formulations suitable for subcutaneous delivery. Consequently, crovalimab offers a four-weekly subcutaneous injection regimen for PNH, marking a substantial improvement in treatment convenience and potentially transforming patients' quality of life.
循环抗体的出现，利用了 pH 依赖性抗原结合和优化的 FcRn 相互作用，推动了抗体治疗领域的发展，使抗体的持久性延长，剂量减少。依库珠单抗（Soliris）证明了 C5 抑制剂在阵发性夜间血红蛋白尿症（PNH）中的疗效，而其衍生物拉维珠单抗（Ultomiris）作为一种循环抗体，延长了给药间隔。然而，包括静脉给药和对 C5 中 R885H 单核苷酸多态性（SNP）患者无效在内的局限性，可能需要替代解决方案。克罗瓦单抗（PiaSky）是一种新一代的循环抗体，通过创新的电荷工程克服了这些挑战，实现了 C5-克罗瓦单抗复合物的细胞摄取增强，并针对独特的 C5 表位，无论 R885H SNP 如何，均可实现疗效。本研究强调了克罗瓦单抗独特的分子特征，表明其消除了与 Fcγ 受体和 C1q 的结合，同时优化了抗原结合特性。电荷工程的影响在小鼠中得到了再次证实，表明其 C5 清除速度快于循环抗体。值得注意的是，在维持剂量方案中，克罗瓦单抗平均每个抗体中和约七个 C5 分子。此外，其设计还降低了粘度，便于配制适合皮下给药的高浓度制剂。因此，克罗瓦单抗为 PNH 提供了每四周一次的皮下注射方案，在治疗便利性方面有了显著改善，并有可能改善患者的生活质量。
