Yan Hengkang, Vail Mary E, Hii Linda, Guo Nancy, McMurrick Paul J, Oliva Karen, Wilkins Simon, Saha Nayanendu, Nikolov Dimitar B, Lee Fook-Thean, Scott Andrew M, Janes Peter W
Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Australia.
Cancers (Basel). 2022 Jun 28;14(13):3171. doi: 10.3390/cancers14133171.
ADAM10 is a transmembrane metalloprotease that sheds a variety of cell surface proteins, including receptors and ligands that regulate a range of developmental processes which re-emerge during tumour development. While ADAM10 is ubiquitously expressed, its activity is normally tightly regulated, but becomes deregulated in tumours. We previously reported the generation of a monoclonal antibody, 8C7, which preferentially recognises an active form of ADAM10 in human and mouse tumours. We now report our investigation of the mechanism of this specificity, and the preferential targeting of 8C7 to human tumour cell xenografts in mice. We also report the development of novel 8C7 antibody-drug conjugates that preferentially kill cells displaying the 8C7 epitope, and that can inhibit tumour growth in mice. This study provides the first demonstration that antibody-drug conjugates targeting an active conformer of ADAM10, a widely expressed transmembrane metalloprotease, enable tumour-selective targeting and inhibition.
ADAM10是一种跨膜金属蛋白酶，可切割多种细胞表面蛋白，包括调节一系列发育过程的受体和配体，这些过程在肿瘤发生时会再次出现。虽然ADAM10在全身广泛表达，但其活性通常受到严格调控，但在肿瘤中会失调。我们之前报道了一种单克隆抗体8C7的产生，它优先识别在人和小鼠肿瘤中ADAM10的活性形式。我们现在报告我们对这种特异性机制的研究，以及8C7在小鼠体内对人肿瘤细胞异种移植的优先靶向作用。我们还报告了新型8C7抗体-药物偶联物的开发，该偶联物优先杀死显示8C7表位的细胞，并能抑制小鼠肿瘤生长。这项研究首次证明，靶向广泛表达的跨膜金属蛋白酶ADAM10活性构象的抗体-药物偶联物能够实现肿瘤选择性靶向和抑制。
