Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma.
Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma.
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DOI：
10.1158/1535-7163.mct-21-0836
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发表时间：
2022-06-01
影响因子：
5.7
通讯作者：
Gorlick, Richard
中科院分区：
文献类型：
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作者：
Wang, Yifei;Tian, Xiangjun;Zhang, Wendong;Zhang, Zhongting;Lazcano, Rossana;Hingorani, Pooja;Roth, Michael E.;Gill, Jonathan D.;Harrison, Douglas J.;Xu, Zhaohui;Jusu, Sylvester;Kannan, Sankaranarayanan;Wang, Jing;Lazar, Alexander J.;Earley, Eric J.;Erickson, Stephen W.;Gelb, Tara;Huxley, Philip;Lahdenranta, Johanna;Mudd, Gemma;Kurmasheva, Raushan T.;Houghton, Peter J.;Smith, Malcolm A.;Kolb, Edward A.;Gorlick, Richard
针对细胞表面抗原的免疫结合物已经显示出临床活性，能够在几种实体和血液系统恶性肿瘤中获得监管批准。我们假设，一种严格和全面的表面组分析方法来识别骨肉瘤特异性细胞表面抗原，同样可以使这种疾病的有效治疗方法的发展成为可能。在这里，我们描述了一种整合的蛋白质组和转录切割表面组谱方法来识别在骨肉瘤中高表达但在正常组织中表达最低的细胞表面蛋白。使用这种方法，我们确定了在骨肉瘤中高表达的靶点。三个靶点，MT1-MMP，CD276和MRC2，被证实在骨肉瘤中过表达。此外，我们在骨肉瘤患者来源的异种移植模型中测试了BT1769，一种MT1-MMP靶向自行车毒素结合物。结果表明，BT1769具有良好的抗肿瘤活性，与靶标亲和力高，具有良好的药动学特征。这证实了这样的假设，即我们的方法确定了具有显著治疗潜力的骨肉瘤新靶点。
Immunoconjugates targeting cell-surface antigens have demonstrated clinical activity to enable regulatory approval in several solid and hematologic malignancies. We hypothesize that a rigorous and comprehensive surfaceome profiling approach to identify osteosarcoma-specific cell-surface antigens can similarly enable development of effective therapeutics in this disease. Herein, we describe an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. Using this approach, we identified targets that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Furthermore, we tested BT1769, an MT1-MMP–targeted Bicycle toxin conjugate, in osteosarcoma patient-derived xenograft models. The results showed that BT1769 had encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that our approach identifies novel targets with significant therapeutic potential in osteosarcoma.