Antibody-Drug Conjugates Targeting the Urokinase Receptor (uPAR) as a Possible Treatment of Aggressive Breast Cancer

IF 3 Q3 IMMUNOLOGY

Antibodies Pub Date : 2019-11-05 DOI:10.3390/antib8040054

E. Harel, Penelope M. Drake, Robyn M. Barfield, Irene Lui, S. Farr-Jones, L. V. van’t Veer, Zev J. Gartner, E. Green, André L. Lourenço, Yifan Cheng, B. Hann, David Rabuka, C. Craik

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引用次数: 13

Abstract

A promising molecular target for aggressive cancers is the urokinase receptor (uPAR). A fully human, recombinant antibody that binds uPAR to form a stable complex that blocks uPA-uPAR interactions (2G10) and is internalized primarily through endocytosis showed efficacy in a mouse xenograft model of highly aggressive, triple negative breast cancer (TNBC). Antibody-drug conjugates (ADCs) of 2G10 were designed and produced bearing tubulin inhibitor payloads ligated through seven different linkers. Aldehyde tag technology was employed for linking, and either one or two tags were inserted into the antibody heavy chain, to produce site-specifically conjugated ADCs with drug-to-antibody ratios of either two or four. Both cleavable and non-cleavable linkers were combined with two different antimitotic toxins—MMAE (monomethylauristatin E) and maytansine. Nine different 2G10 ADCs were produced and tested for their ability to target uPAR in cell-based assays and a mouse model. The anti-uPAR ADC that resulted in tumor regression comprised an MMAE payload with a cathepsin B cleavable linker, 2G10-RED-244-MMAE. This work demonstrates in vitro activity of the 2G10-RED-244-MMAE in TNBC cell lines and validates uPAR as a therapeutic target for TNBC.

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靶向尿激酶受体（uPAR）的抗体-药物偶联物可能治疗侵袭性乳腺癌症

尿激酶受体(uPAR)是治疗侵袭性癌症的一个很有前景的分子靶点。一种完全人源的重组抗体结合uPAR形成稳定复合物，阻断uPA-uPAR相互作用(2G10)，并主要通过内吞作用内化，在高侵袭性三阴性乳腺癌(TNBC)小鼠异种移植模型中显示出疗效。设计并制备了2G10的抗体-药物偶联物(adc)，通过7种不同的连接物连接微管蛋白抑制剂有效载荷。采用醛标签技术进行连接，将一个或两个标签插入抗体重链中，得到药抗比为2或4的位点特异性偶联adc。可切割和不可切割的连接体都与两种不同的抗有丝分裂毒素mmae(单甲基月桂化酶E)和美塔辛结合。生产了9种不同的2G10 adc，并在基于细胞的测定和小鼠模型中测试了它们靶向uPAR的能力。导致肿瘤消退的抗upar ADC包括一个带有组织蛋白酶B可切割连接体2G10-RED-244-MMAE的MMAE有效载荷。这项工作证明了2G10-RED-244-MMAE在TNBC细胞系中的体外活性，并验证了uPAR作为TNBC的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Antibodies IMMUNOLOGY-

CiteScore

7.10

自引率

6.40%

发文量

审稿时长

11 weeks

期刊介绍： Antibodies (ISSN 2073-4468), an international, peer-reviewed open access journal which provides an advanced forum for studies related to antibodies and antigens. It publishes reviews, research articles, communications and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided. Electronic files or software regarding the full details of the calculation and experimental procedure - if unable to be published in a normal way - can be deposited as supplementary material. This journal covers all topics related to antibodies and antigens, topics of interest include (but are not limited to): antibody-producing cells (including B cells), antibody structure and function, antibody-antigen interactions, Fc receptors, antibody manufacturing antibody engineering, antibody therapy, immunoassays, antibody diagnosis, tissue antigens, exogenous antigens, endogenous antigens, autoantigens, monoclonal antibodies, natural antibodies, humoral immune responses, immunoregulatory molecules.