PDF(Pubmed)
Abstract：
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 in silico 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.
摘要：
用于自动注射器装置的低剂量体积的高浓度单克隆抗体(mAb)溶液的制剂由于升高的溶液粘度而在可制造性和患者施用方面提出了挑战。通常会发现许多治疗有效的单克隆抗体，但是他们的商业发展因不利的可发展性挑战而停滞不前。在这项工作中,我们提出了一个系统的实验框架，用于分子描述符的计算筛选，以指导24个突变体的设计，这些突变体具有修改的粘度曲线，并伴随着实验评估。我们使用模型抗IL8mAb和八个工程突变变体进行的实验观察表明，疏水相互作用的位置会影响粘度降低。而靶向带正电荷的贴剂与野生型抗IL-8mAb相比显著增加粘度。我们得出的结论是，大多数预测的计算机理化性质与具有次优显影特性的抗体的测量实验参数相关性较差，强调需要对单克隆抗体进行全面的个案评估。该框架将分子设计和分类通过计算预测与实验评估相结合，有助于灵活合理地设计具有定制溶液粘度的mAb。确保在自我管理方案中提高可制造性和患者便利性。
