Comprehensive assessments of pharmacokinetics and immunogenicity of farletuzumab ecteribulin, a novel antibody-drug conjugate against tumors expressing folate receptor α, in monkeys

IF 3.1 3区医学 Q2 CHEMISTRY, ANALYTICAL

Journal of pharmaceutical and biomedical analysis Pub Date : 2025-07-26 DOI:10.1016/j.jpba.2025.117084

Shawn Fernando , Yuji Mano

{"title":"Comprehensive assessments of pharmacokinetics and immunogenicity of farletuzumab ecteribulin, a novel antibody-drug conjugate against tumors expressing folate receptor α, in monkeys","authors":"Shawn Fernando , Yuji Mano","doi":"10.1016/j.jpba.2025.117084","DOIUrl":null,"url":null,"abstract":"<div><div>Farletuzumab ecteribulin (MORAb-202) is a novel antibody-drug conjugate (ADC) comprising farletuzumab and eribulin with a cathepsin-B cleavable linker, currently under development for tumors expressing folate receptor α. It is crucial to comprehend the pharmacokinetics (PK) of MORAb-202 in monkeys to enhance the accuracy of PK prediction in humans. To this end, a series of assays were devised for the total antibody (Tab) as the sum of conjugated and unconjugated antibodies, the conjugated antibody as the ADC, and the unconjugated eribulin (payload) by a ligand binding assay (LBA) and liquid chromatography with tandem mass spectrometry. The LBA by Gyrolab was employed for the quantification of Tab and ADC. Additionally, a semi-quantitative assay for anti-drug antibody (ADA) was developed using the LBA for the immunogenicity assessment. The quantifiable range for ADC and Tab in monkey serum was from 0.4 and 4 µg/mL, respectively, while eribulin was quantified from 0.2 ng/mL. The aforementioned methodologies were subsequently validated and employed in a PK study in monkeys. The accuracy and precision of the assay were within the criteria. Following intravenous administration, the PK profiles of Tab and ADC were similar, while minimal levels of eribulin. No ADA against MORAb-202 was detected in postdose samples.</div></div>","PeriodicalId":16685,"journal":{"name":"Journal of pharmaceutical and biomedical analysis","volume":"266 ","pages":"Article 117084"},"PeriodicalIF":3.1000,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmaceutical and biomedical analysis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S073170852500425X","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, ANALYTICAL","Score":null,"Total":0}

引用次数: 0

Abstract

Farletuzumab ecteribulin (MORAb-202) is a novel antibody-drug conjugate (ADC) comprising farletuzumab and eribulin with a cathepsin-B cleavable linker, currently under development for tumors expressing folate receptor α. It is crucial to comprehend the pharmacokinetics (PK) of MORAb-202 in monkeys to enhance the accuracy of PK prediction in humans. To this end, a series of assays were devised for the total antibody (Tab) as the sum of conjugated and unconjugated antibodies, the conjugated antibody as the ADC, and the unconjugated eribulin (payload) by a ligand binding assay (LBA) and liquid chromatography with tandem mass spectrometry. The LBA by Gyrolab was employed for the quantification of Tab and ADC. Additionally, a semi-quantitative assay for anti-drug antibody (ADA) was developed using the LBA for the immunogenicity assessment. The quantifiable range for ADC and Tab in monkey serum was from 0.4 and 4 µg/mL, respectively, while eribulin was quantified from 0.2 ng/mL. The aforementioned methodologies were subsequently validated and employed in a PK study in monkeys. The accuracy and precision of the assay were within the criteria. Following intravenous administration, the PK profiles of Tab and ADC were similar, while minimal levels of eribulin. No ADA against MORAb-202 was detected in postdose samples.

查看原文本刊更多论文

farletuzumab ecteribulin是一种新型抗体-药物偶联物，用于抗表达叶酸受体α的肿瘤，在猴子体内的药代动力学和免疫原性的综合评估

Farletuzumab ecteribulin （MORAb-202）是一种新型抗体-药物偶联物（ADC），由Farletuzumab和eribulin以及cathepsinb可切割连接体组成，目前正在开发用于表达叶酸受体α的肿瘤。了解MORAb-202在猴体内的药代动力学（PK）对提高其在人体内药代动力学预测的准确性至关重要。为此，采用配体结合法（LBA）和液相色谱串联质谱法对总抗体（Tab）（偶联抗体和非偶联抗体的总和）、偶联抗体（ADC）和非偶联艾瑞布林（有效载荷）进行了一系列检测。采用Gyrolab的LBA法定量Tab和ADC。此外，利用LBA建立了抗药物抗体（ADA）的半定量检测方法，用于免疫原性评价。猴子血清中ADC和Tab的定量范围分别为0.4和4 µg/mL，而埃瑞布林的定量范围为0.2 ng/mL。上述方法随后在猴子的PK研究中得到验证和应用。测定的准确度和精密度均在标准范围内。静脉给药后，Tab和ADC的PK谱相似，而伊瑞布林的水平最低。在给药后样品中未检测到针对MORAb-202的ADA。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of pharmaceutical and biomedical analysis 医学-分析化学

CiteScore

6.70

自引率

5.90%

发文量

588

审稿时长

37 days

期刊介绍： This journal is an international medium directed towards the needs of academic, clinical, government and industrial analysis by publishing original research reports and critical reviews on pharmaceutical and biomedical analysis. It covers the interdisciplinary aspects of analysis in the pharmaceutical, biomedical and clinical sciences, including developments in analytical methodology, instrumentation, computation and interpretation. Submissions on novel applications focusing on drug purity and stability studies, pharmacokinetics, therapeutic monitoring, metabolic profiling; drug-related aspects of analytical biochemistry and forensic toxicology; quality assurance in the pharmaceutical industry are also welcome. Studies from areas of well established and poorly selective methods, such as UV-VIS spectrophotometry (including derivative and multi-wavelength measurements), basic electroanalytical (potentiometric, polarographic and voltammetric) methods, fluorimetry, flow-injection analysis, etc. are accepted for publication in exceptional cases only, if a unique and substantial advantage over presently known systems is demonstrated. The same applies to the assay of simple drug formulations by any kind of methods and the determination of drugs in biological samples based merely on spiked samples. Drug purity/stability studies should contain information on the structure elucidation of the impurities/degradants.