Improved Inhibition of Tumor Growth by Diabody-Drug Conjugates via Half-Life Extension
Improved Inhibition of Tumor Growth by Diabody-Drug Conjugates via Half-Life Extension
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DOI：
10.1021/acs.bioconjchem.9b00170
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发表时间：
2019-04-01
影响因子：
4.7
通讯作者：
Borrok, M. Jack
中科院分区：
文献类型：
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作者：
Li, Qing;Barrett, Allison;Borrok, M. Jack
尽管抗体-药物缀合物（ADC）在患有实体瘤和血液恶性肿瘤的患者中取得了一些临床成功，但由于这些化合物的窄治疗窗，ADC设计的改进仍然是期望的。肿瘤靶向抗体片段具有优于单克隆抗体的明显优势，包括更快速的肿瘤积聚和增强的渗透，但易于快速清除。半衰期延长技术，如聚乙二醇化和白蛋白结合结构域（ABD）已被广泛用于改善许多不同类型生物制剂的药代动力学。PEG化通过增加流体动力学尺寸以降低肾清除率来改善药代动力学，而ABD通过FcRn介导的再循环来延长半衰期。在这项研究中，我们使用了一种抗癌胚抗原5 T4双抗体与一个高度有效的细胞毒性吡咯并苯并二氮杂卓（PBD）弹头共轭，以评估和比较的影响，聚乙二醇化和白蛋白结合抗体片段药物共轭物的体内疗效。2x PEG 20 K与双抗体的缀合将半衰期从40分钟改善至33小时，并且ABD-双抗体融合蛋白在小鼠中表现出45小时的半衰期。在乳腺癌MDA-MB-436的异种移植模型中，ABD-双抗体-PBD显示出比PEG-双抗体-PBD或双抗体-PBD更大的肿瘤生长抑制和更好的耐受性。这些结果表明，半衰期延长的机制是设计细胞毒性抗肿瘤药物的重要考虑因素。
Despite some clinical success with antibody-drug conjugates (ADCs) in patients with solid tumors and hematological malignancies, improvements in ADC design are still desirable due to the narrow therapeutic window of these compounds. Tumor-targeting antibody fragments have distinct advantages over monoclonal antibodies, including more rapid tumor accumulation and enhanced penetration, but are subject to rapid clearance. Half-life extension technologies such as PEGylation and albumin-binding domains (ABDs) have been widely used to improve the pharmacokinetics of many different types of biologics. PEGylation improves pharmacokinetics by increasing hydrodynamic size to reduce renal clearance, whereas ABDs extend half-life via FcRn-mediated recycling. In this study, we used an anti-oncofetal antigen 5T4 diabody conjugated with a highly potent cytotoxic pyrrolobenzodiazepine (PBD) warhead to assess and compare the effects of PEGylation and albumin binding on the in vivo efficacy of antibody fragment drug conjugates. Conjugation of 2x PEG20K to a diabody improved half-life from 40 min to 33 h, and an ABD-diabody fusion protein exhibited a half-life of 45 h in mice. In a xenograft model of breast cancer MDA-MB-436, the ABD-diabody-PBD showed greater tumor growth suppression and better tolerability than either PEG-diabody-PBD or diabody-PBD. These results suggest that the mechanism of half-life extension is an important consideration for designing cytotoxic antitumor agents.