School of Pharmaceutical Sciences, University of Geneva, CMU, Rue Michel Servet 1, Geneva 1211, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU, Rue Michel Servet 1, Geneva 1211, Switzerland.
Pharmacy, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
J Pharm Biomed Anal. 2024 Dec 15;251:116410. doi: 10.1016/j.jpba.2024.116410. Epub 2024 Aug 15.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new therapeutic approach for patients with peritoneal cancer. So far, most published studies investigated the administration of established cytostatic agents through PIPAC. This study aimed to evaluate the effect of PIPAC on two breakthrough anti-cancer agents, specifically anti-PD1 pembrolizumab, and anti-HER2 antibody-drug conjugate (ADC) - trastuzumab-deruxtecan. We conducted systematic analyses on samples of pembrolizumab and trastuzumab-deruxtecan at clinically relevant concentrations before and after PIPAC administration using an experimental setup of a hermetic container system, mimicking the abdominal cavity and using identical features as in clinical use. We utilized a range of chromatographic and spectroscopic techniques to explore potential alterations in the primary, secondary, and tertiary structures of the drugs, focusing on post-translational modifications resulting from the aerosolization. Our findings indicate that PIPAC did not compromise the integrity of tested biopharmaceuticals. The size variants of both drugs, assessed by size exclusion chromatography (SEC), remained unchanged. Reversed-phase liquid chromatography (RPLC) and hydrophobic interaction chromatography (HIC) revealed no significant differences in hydrophobicity variants, the average drug-to-antibody ratio (DAR), or DAR distribution before and after PIPAC treatment. Circular dichroism (CD) spectroscopy confirmed that the secondary and tertiary structures were preserved. While pembrolizumab showed no change in charge variants post-PIPAC, trastuzumab-deruxtecan exhibited a non-negligible change in the quantity of charge variants on the monoclonal antibody itself, while the payload remained unchanged. This shift could possibly be related to the metallic composition of the CapnoPen® device (made of nickel and chromium) used in PIPAC and for these experiments. Together, our results suggest that PIPAC does not alter the structure of pembrolizumab and trastuzumab-deruxtecan, paving the way for future clinical trials.
腹腔内压力气溶胶化疗（PIPAC）是一种治疗腹膜癌患者的新方法。到目前为止，大多数已发表的研究都通过 PIPAC 研究了既定细胞抑制剂的给药。本研究旨在评估 PIPAC 对两种突破性抗癌药物，即抗 PD1 派姆单抗和抗 HER2 抗体药物偶联物（ADC）-曲妥珠单抗-deruxtecan 的影响。我们使用模拟腹腔并使用与临床使用相同特征的密封容器系统的实验装置，在临床相关浓度下对派姆单抗和曲妥珠单抗 - deruxtecan 样本进行了系统分析。我们利用一系列色谱和光谱技术来探索药物的一级、二级和三级结构的潜在变化，重点关注气溶胶化导致的翻译后修饰。我们的研究结果表明，PIPAC 没有损害测试生物制药的完整性。通过尺寸排阻色谱（SEC）评估的两种药物的大小变异体保持不变。反相液相色谱（RPLC）和疏水相互作用色谱（HIC）显示，在 PIPAC 治疗前后，疏水性变异体、平均药物-抗体比（DAR）或 DAR 分布没有显著差异。圆二色性（CD）光谱证实二级和三级结构得到了保留。虽然派姆单抗在 PIPAC 后电荷变异体没有变化，但曲妥珠单抗 - deruxtecan 单抗本身的电荷变异体数量发生了不可忽略的变化，而有效载荷保持不变。这种变化可能与 PIPAC 中使用的 CapnoPen®设备（由镍和铬制成）和这些实验的金属组成有关。总之，我们的结果表明 PIPAC 不会改变派姆单抗和曲妥珠单抗 - deruxtecan 的结构，为未来的临床试验铺平了道路。
