Phage Display Selection, In Vitro Characterization, and Correlative PET Imaging of a Novel HER3 Peptide.
Phage Display Selection, In Vitro Characterization, and Correlative PET Imaging of a Novel HER3 Peptide.
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DOI：
10.1007/s11307-017-1106-6
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发表时间：
2018-04
影响因子：
3.1
通讯作者：
Mahmood U
中科院分区：
文献类型：
--
作者：
Larimer BM;Phelan N;Wehrenberg-Klee E;Mahmood U
HER3 （ERBB3）是一种受体酪氨酸激酶，与多种癌症的治疗耐药有关，包括乳腺癌、肺癌和前列腺癌。靶向治疗后HER3的过表达可以在单个病变和转移部位内迅速和异质性地发生，这使得活检的蛋白定量非常具有挑战性。一种全球性的、非侵入性的方法，如正电子发射断层扫描（PET）成像，可以对HER3进行串行量化，为在治疗前后监测整个肿瘤负荷中的HER3表达提供了一种有用的方法。HER3表达的PET成像除了为临床试验患者选择针对HER3的新疗法提供信息外，还可以通过检测HER3介导的耐药性，从而允许更个性化的靶向治疗方法。针对HER3细胞外结构域的噬菌体展示选择是为了开发具有最佳血液清除率和高度准确的HER3定量的肽。结果表明，该肽序列与HER3结合的亲和力为270±151 nM。这种肽被称为HER3P1，与其他类似的酪氨酸受体激酶如EGFR和HER2相比，可以高选择性地与HER3结合。此外，HER3P1能够在体外区分her3高表达和低表达的细胞。用Ga-68对该肽进行放射性标记，并通过体内PET成像证明其特异性结合HER3。[68Ga]HER3P1的摄取对her3阳性肿瘤具有高度特异性，肿瘤与背景的比值为1.59-3.32，而her3阴性肿瘤的比值为0.84-0.93。经Western blot定量和生物分布证实，[68Ga]HER3P1的摄取也与蛋白表达高度相关（P < 0.001）。HER3P1通过PET成像准确量化HER3的表达，具有作为临床显像剂的潜在用途。
HER3 (ERBB3) is a receptor tyrosine kinase that is implicated in treatment resistance across multiple cancers, including those of the breast, lung, and prostate. Overexpression of HER3 following targeted therapy can occur rapidly and heterogeneously both within a single lesion and across sites of metastasis, making protein quantification by biopsy highly challenging. A global, noninvasive methodology such as positron emission tomography (PET) imaging can permit serial quantification of HER3, providing a useful approach to monitor HER3 expression across the entire tumor burden both prior to and following treatment. PET imaging of HER3 expression may permit a more personalized approach to targeted therapy by allowing for detection of HER3-mediated resistance, in addition to informing clinical trial patient selection for novel therapies targeting HER3. Phage display selection targeting the HER3 extracellular domain was performed in order to develop a peptide with optimal blood clearance and highly accurate HER3 quantification. The selection converged to a consensus peptide sequence that was subsequently found to bind HER3 with an affinity of 270 ± 151 nM. The peptide, termed HER3P1, was bound with high selectivity to HER3 over other similar receptor tyrosine kinases such as EGFR and HER2. Furthermore, HER3P1 was able to distinguish between high and low HER3-expressing cells in vitro. The peptide was radiolabeled with Ga-68 and demonstrated to specifically bind HER3 by in vivo PET imaging. Uptake of [68Ga]HER3P1 was highly specific for HER3-positive tumors, with tumor-to background ratios ranging from 1.59–3.32, compared to those of HER3-negative tumors, ranging from 0.84–0.93. The uptake of [68Ga]HER3P1 also demonstrated high (P < 0.001) correlation with protein expression as quantified by Western blot and confirmed by biodistribution. HER3P1 accurately quantifies expression of HER3 by PET imaging and has potential utility as a clinical imaging agent.
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影响因子：
62.1
作者：
Deutscher, Susan L.
通讯作者：
Deutscher, Susan L.
游离生长抑素受体分数预测了奥曲肽在神经内分泌肿瘤模型中的抗增生作用：对剂量优化的影响。
影响因子：
11.2
作者：
Heidari P;Wehrenberg-Klee E;Habibollahi P;Yokell D;Kulke M;Mahmood U
通讯作者：
Mahmood U
DOI：
10.1023/a:1019749504418
发表时间：
2002-05-01
期刊：
JOURNAL OF PROTEIN CHEMISTRY
影响因子：
--
作者：
Karasseva, NG;Glinsky, VV;Quinn, TP
通讯作者：
Quinn, TP
影响因子：
46.9
作者：
Lidke, DS;Nagy, P;Jovin, TM
通讯作者：
Jovin, TM
影响因子：
9.3
作者：
Wehrenberg-Klee, Eric;Turker, N. Selcan;Mahmood, Umar
通讯作者：
Mahmood, Umar