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联合给药的抗体可提高抗体-药物偶联物进入人类癌症的穿透力。

Co-administered antibody improves penetration of antibody-dye conjugate into human cancers with implications for antibody-drug conjugates.

机构信息

Department of Otolaryngology - Head and Neck Surgery, Stanford University School of Medicine, 900 Blake Wilbur Drive, Stanford, CA, 94305, USA.

Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

出版信息

Nat Commun. 2020 Nov 9;11(1):5667. doi: 10.1038/s41467-020-19498-y.

Abstract

Poor tissue penetration remains a major challenge for antibody-based therapeutics of solid tumors, but proper dosing can improve the tissue penetration and thus therapeutic efficacy of these biologics. Due to dose-limiting toxicity of the small molecule payload, antibody-drug conjugates (ADCs) are administered at a much lower dose than their parent antibodies, which further reduces tissue penetration. We conducted an early-phase clinical trial (NCT02415881) and previously reported the safety of an antibody-dye conjugate (panitumumab-IRDye800CW) as primary outcome. Here, we report a retrospective exploratory analysis of the trial to evaluate whether co-administration of an unconjugated antibody could improve the intratumoral distribution of the antibody-dye conjugate in patients. By measuring the multiscale distribution of the antibody-dye conjugate, this study demonstrates improved microscopic antibody distribution without increasing uptake (toxicity) in healthy tissue when co-administered with the parent antibody, supporting further clinical investigation of the co-administration dosing strategy to improve the tumor penetration of ADCs.

摘要

对于实体瘤的抗体治疗药物来说,组织穿透性差仍然是一个主要挑战,但适当的给药剂量可以提高这些生物制剂的组织穿透性和治疗效果。由于小分子有效载荷的剂量限制毒性,抗体药物偶联物(ADC)的给药剂量远低于其母体抗体,这进一步降低了组织穿透性。我们进行了一项早期临床试验(NCT02415881),并以前报告了抗体染料偶联物(panitumumab-IRDye800CW)的安全性作为主要结果。在这里,我们报告了该试验的回顾性探索性分析,以评估联合使用未缀合抗体是否可以改善抗体染料偶联物在患者中的肿瘤内分布。通过测量抗体染料偶联物的多尺度分布,这项研究表明,当与母体抗体联合使用时,即使在不增加健康组织摄取(毒性)的情况下,也可以改善微观抗体分布,支持进一步临床研究联合给药剂量策略以提高 ADC 的肿瘤穿透性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a52b/7652891/a9f7aed86a67/41467_2020_19498_Fig1_HTML.jpg

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