Discovery of antibodies and cognate surface targets for ovarian cancer by surface profiling.
Discovery of antibodies and cognate surface targets for ovarian cancer by surface profiling.
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DOI：
10.1073/pnas.2206751120
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发表时间：
2023-01-03
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
用于开发抗体导向疗法的靶标选择通常由特定假设驱动或基于表达谱分析，这需要费力的实验验证。我们开发了一个合并的筛选平台，用于在单一筛选中无偏倚地高通量鉴定多个癌症特异性靶点。应用该技术导致在卵巢癌中鉴定多个治疗靶点候选者。除了选择细胞类型特异性靶标外，该平台还可以同时发现具有治疗潜力的抗体，从而避免了冗长的抗体发现活动。尽管靶向特异性肿瘤表达抗原的抗体是一些癌症的护理标准，但鉴定适合抗体结合的癌症特异性靶标仍然是开发新疗法的瓶颈。为了克服这一挑战，我们开发了一种高通量平台，该平台允许基于表型结合谱无偏地同时发现抗体和靶标。将该平台应用于卵巢癌，我们使用基因组学、流式细胞术和质谱法在单轮筛选中鉴定了多种癌症靶点，包括受体酪氨酸激酶、粘附和迁移蛋白、蛋白酶和调节血管生成的蛋白质。特别是，我们确定BCAM作为高级别浆液性卵巢癌靶向治疗的一个有前途的候选者。更一般地说，这种方法提供了一个快速和灵活的框架来识别癌症靶标和抗体。
Target selection for the development of antibody-directed therapies is commonly driven by a specific hypothesis or based on expression profile analysis, which require laborious experimental validation. We developed a pooled screening platform for the unbiased, high-throughput identification of multiple cancer-specific targets in a single screen. Applying this technology resulted in the identification of multiple therapeutic target candidates in ovarian cancer. In addition to the selection of cell type-specific targets, the platform simultaneously allows the discovery of antibodies with therapeutic potential, thereby bypassing the need for lengthy antibody discovery campaigns. Although antibodies targeting specific tumor-expressed antigens are the standard of care for some cancers, the identification of cancer-specific targets amenable to antibody binding has remained a bottleneck in development of new therapeutics. To overcome this challenge, we developed a high-throughput platform that allows for the unbiased, simultaneous discovery of antibodies and targets based on phenotypic binding profiles. Applying this platform to ovarian cancer, we identified a wide diversity of cancer targets including receptor tyrosine kinases, adhesion and migration proteins, proteases and proteins regulating angiogenesis in a single round of screening using genomics, flow cytometry, and mass spectrometry. In particular, we identified BCAM as a promising candidate for targeted therapy in high-grade serous ovarian cancers. More generally, this approach provides a rapid and flexible framework to identify cancer targets and antibodies.
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DOI：
10.1073/pnas.1501735112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Kannan, Kalpana;Coarfa, Cristian;Yen, Laising
通讯作者：
Yen, Laising
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
DOI：
10.1093/bioinformatics/bts565
发表时间：
2012-12-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Fu L;Niu B;Zhu Z;Wu S;Li W
通讯作者：
Li W
影响因子：
2.9
作者：
Kikkawa, Y;Miner, JH
通讯作者：
Miner, JH