Therapeutic monoclonal antibodies (mAbs) are commonly administered to patients through intravenous (IV) infusion, which involves diluting the medication into an infusion solution (e.g., saline and 5% dextrose). Using the wrong diluent can cause product aggregation, which may compromise patient safety. We and others have shown that Herceptin® (trastuzumab) and Avastin® (bevacizumab) undergo rapid aggregation upon mixing with dextrose and human plasma in vitro. In this study, we evaluated the compatibility of a panel of 11 therapeutic mAbs with dextrose or saline and human serum. These mAbs were randomly selected for their distinct formulations and IgG isotypes (IgG1, IgG2, IgG4, and Fc-fusion protein). All the mAbs appeared to be compatible with saline and human serum. However, mAbs that were formulated at acidic pH (≤ 6.5) exclusively formed insoluble aggregates upon mixing with dextrose and serum. Such aggregation was not detected for the mAbs that are at neutral pH (7.2-7.5) or in buffers containing sodium chloride. Mass spectrometric analysis revealed that the insoluble aggregates were composed of mAb molecules and several serum proteins (e.g., complement proteins, apolipoprotein, fibronectin) that are characterized by an isoelectric point of pH 5.4-6.7. At proximate pH to the isoelectric point values, those abundant serum proteins appeared to undergo isoelectric precipitation with mAb molecules. Our observations highlight a potential risk of protein aggregation at the blood-IV interface if a diluent is incompatible with a specific mAb formulation. This information has implications in guiding the design of product formulations and the selection of the right diluent for intravenous infusion of therapeutic mAbs.Abbreviations: ADC: antibody-drug conjugate; D5W: 5% dextrose in water; IM: intramuscular; IV: intravenous; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mAb: monoclonal antibody; SC: subcutaneous; pI: isoelectric point.

中文翻译：

---

定义用于治疗性抗体静脉输注的正确稀释剂。

治疗性单克隆抗体（mAb）通常通过静脉内（IV）输注给予患者，这涉及将药物稀释到输注溶液中（例如，盐水和5％葡萄糖）。使用错误的稀释剂会导致产品聚集，从而可能危及患者的安全。我们和其他人已经表明，赫赛汀®（曲妥珠单抗）和阿瓦斯汀®（贝伐单抗）在与葡萄糖和体外人血浆混合后会迅速聚集。在这项研究中，我们评估了11种治疗性mAb与右旋糖或生理盐水以及人血清的相容性。随机选择这些mAb，因为它们具有独特的配方和IgG同种型（IgG1，IgG2，IgG4和Fc融合蛋白）。所有的单克隆抗体似乎都与盐水和人血清相容。但是，在酸性pH（≤6）下配制的mAb。5）与葡萄糖和血清混合后，专门形成的不溶性聚集体。对于中性pH（7.2-7.5）或含有氯化钠的缓冲液中的mAb，未检测到这种聚集。质谱分析显示，不溶性聚集体由mAb分子和几种血清蛋白（例如补体蛋白，载脂蛋白，纤连蛋白）组成，其特征在于等电点的pH值为5.4-6.7。在接近等电点值的pH值下，那些丰富的血清蛋白似乎与mAb分子发生等电沉淀。我们的观察结果表明，如果稀释剂与特定的mAb制剂不兼容，则血液-IV界面处蛋白质聚集的潜在风险。该信息对指导产品配方的设计以及为治疗性mAb静脉输注正确的稀释剂的选择具有指导意义。D5W：5％的葡萄糖水溶液；IM：肌内；IV：静脉内；LC-MS / MS：液相色谱-串联质谱； LC-MS / MS。mAb：单克隆抗体；SC：皮下；pI：等电点。