Armstrong Georgina B, Shah Vidhi, Sanches Paula, Patel Mitul, Casey Ricky, Jamieson Craig, Burley Glenn A, Lewis William, Rattray Zahra
Drug Substance Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, UK.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Comput Struct Biotechnol J. 2024 May 24;23:2345-2357. doi: 10.1016/j.csbj.2024.05.041. eCollection 2024 Dec.
The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. Often many therapeutically potent mAbs are discovered, but their commercial development is stalled by unfavourable developability challenges. In this work, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of 24 mutants with modified viscosity profiles accompanied by experimental evaluation. Our experimental observations using a model anti-IL8 mAb and eight engineered mutant variants reveal that viscosity reduction is influenced by the location of hydrophobic interactions, while targeting positively charged patches significantly increases viscosity in comparison to wild-type anti-IL-8 mAb. We conclude that most predicted physicochemical properties exhibit poor correlation with measured experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the need for comprehensive case-by-case evaluation of mAbs. This framework combining molecular design and triage via computational predictions with experimental evaluation aids the agile and rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios.
为自动注射器装置配制低剂量体积的高浓度单克隆抗体(mAb)溶液,由于溶液粘度升高,在可制造性和患者给药方面带来了挑战。通常会发现许多具有治疗潜力的单克隆抗体,但它们的商业开发因不利的可开发性挑战而停滞不前。在这项工作中,我们提出了一个系统的实验框架,用于对分子描述符进行计算筛选,以指导设计24种具有改良粘度曲线的突变体,并进行实验评估。我们使用模型抗IL8单克隆抗体和8种工程突变体变体的实验观察结果表明,粘度降低受疏水相互作用位置的影响,而与野生型抗IL-8单克隆抗体相比,靶向带正电荷的区域会显著增加粘度。我们得出结论,对于具有次优可开发性特征的抗体,大多数预测的物理化学性质与测量的实验参数之间的相关性较差,这强调了对单克隆抗体进行全面逐案评估的必要性。这个结合分子设计和通过计算预测进行分类并辅以实验评估的框架,有助于灵活、合理地设计具有定制溶液粘度的单克隆抗体,确保在自我给药场景中提高可制造性并方便患者使用。