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首页> 美国卫生研究院文献>Antibodies >Multiplex LC-MS/MS Assays for Clinical Bioanalysis of MEDI4276 an Antibody-Drug Conjugate of Tubulysin Analogue Attached via Cleavable Linker to a Biparatopic Humanized Antibody against HER-2
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Multiplex LC-MS/MS Assays for Clinical Bioanalysis of MEDI4276 an Antibody-Drug Conjugate of Tubulysin Analogue Attached via Cleavable Linker to a Biparatopic Humanized Antibody against HER-2

机译：用于医学生物学分析的MEDI4276的多重LC-MS / MS分析MEDI4276是一种通过可切割接头连接至抗HER-2双原位人源化抗体的Tubulysin类似物的抗体-药物偶联物

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Bioanalysis of complex biotherapeutics, such as antibody-drug conjugates (ADCs), is challenging and requires multiple assays to describe their pharmacokinetic (PK) profiles. To enable exposure-safety and exposure-efficacy analyses, as well as to understand the metabolism of ADC therapeutics, three bioanalytical methods are typically employed: Total Antibody, Antibody Conjugated Toxin or Total ADC and Unconjugated Toxin. MEDI4276 is an ADC comprised of biparatopic humanized antibody attached via a protease-cleavable peptide-based maleimidocaproyl linker to a tubulysin toxin (AZ13599185) with an approximate average drug-antibody ratio of 4. The conjugated payload of MEDI4276 can undergo ester hydrolysis to produce the conjugated payload AZ13687308, leading to the formation of MEDI1498 (de-acetylated MEDI4276). In this report, we describe the development, validation and application of three novel multiplex bioanalytical methods. The first ligand-binding liquid chromatography coupled with tandem mass spectrometry (LBA-LC-MS/MS) method was developed and validated for simultaneous measurement of total antibody and total ADC (antibody-conjugated AZ13599185) from MEDI4276. The second LBA-LC-MS/MS assay quantified total ADC (antibody-conjugated AZ13687308) from MEDI1498. The third multiplex LC-MS/MS assay was used for simultaneous quantification of unconjugated AZ13599185 and AZ13687308. Additional stability experiments confirmed that quantification of the released warhead in the presence of high concentrations of MEDI4276 was acceptable. Subsequently, the assays were employed in support of a first-in-human clinical trial ().
机译：复杂的生物治疗药物（例如抗体-药物偶联物（ADC））的生物分析具有挑战性，需要多种测定方法来描述其药代动力学（PK）概况。为了进行暴露安全性和暴露效率分析，以及了解ADC治疗药物的代谢，通常采用三种生物分析方法：总抗体，抗体结合毒素或总ADC和未结合毒素。 MEDI4276是一种ADC，由双对位的人源化抗体组成，该抗体通过蛋白酶可裂解的基于肽的马来酰亚胺基己酰基接头与微管溶素毒素（AZ13599185）相连，药物-抗体平均比约为4。​​MEDI4276的共轭有效负载可以进行酯水解以产生共轭有效负载AZ13687308，导致形成MEDI1498（去乙酰化MEDI4276）。在本报告中，我们描述了三种新颖的多重生物分析方法的开发，验证和应用。开发了第一个结合串联质谱的配体结合液相色谱（LBA-LC-MS / MS）方法，并验证了该方法可同时测量来自MEDI4276的总抗体和总ADC（结合抗体的AZ13599185）。第二次LBA-LC-MS / MS分析定量了来自MEDI1498的总ADC（结合抗体的AZ13687308）。第三次多重LC-MS / MS分析用于同时定量未结合的AZ13599185和AZ13687308。额外的稳定性实验证实，在存在高浓度MEDI4276的情况下对释放的战斗部进行定量分析是可以接受的。随后，该测定法被用于支持首次人类临床试验（）。

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