Comparative evaluation of 111In-labeled NOTA-conjugated affibody molecules for visualization of HER3 expression in malignant tumors
Comparative evaluation of 111In-labeled NOTA-conjugated affibody molecules for visualization of HER3 expression in malignant tumors
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DOI：
10.3892/or.2015.4046
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发表时间：
2015-08-01
期刊：
影响因子：
4.2
通讯作者：
Orlova, Anna
中科院分区：
文献类型：
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作者：
Andersson, Ken G.;Rosestedt, Maria;Orlova, Anna
人表皮生长因子受体3型（HER 3）在恶性肿瘤中的表达与多种抗癌治疗的耐药性有关。几种抗HER 3单克隆抗体目前正在进行临床前和临床开发，旨在克服HER 3介导的耐药性。HER 3表达的放射性核素分子成像可以通过允许选择合适的患者进行HER 3靶向治疗来改善治疗。亲和体分子是一类小的（7 kDa）高亲和力靶向蛋白，具有作为分子成像探针的可观潜力。在最近的研究中，我们选择了在低皮摩尔范围内对HER 3具有亲和力的抗体分子。本研究的目的是开发一种适用于放射性金属标记的抗HER 3抗体分子。用铟-111（In-111）标记HEHEHE-Z 08698-NOTA和HEHEHE-Z 08699-NOTA HER 3特异性抗体分子，并使用单光子发射计算机断层扫描（SPECT）在体外和体内评估成像特性。用In-111标记HEHEHE-Z 08698-NOTA和HEHEHE-Z 08699-NOTA提供了稳定的缀合物。体外细胞测试证明两种缀合物与表达HER 3的BT-474乳腺癌细胞特异性结合。在携带BT-474异种移植物的小鼠中，两种缀合物的肿瘤摄取是受体特异性的。In-111-HEHEHE-Z 08698-NOTA和In-111-HEHEHE-Z 08699-NOTA的直接体内比较证明，两种缀合物在肿瘤中提供相等的放射性摄取，尽管In-111-HEHEHE-Z 08698-NOTA的肿瘤-血液比得到改善[注射后12 +/- 3 vs. 8 +/-1.4 h（p.i）]，因为血液清除更有效。In-111-HEHEHE-Z 08698-NOTA是使用SPECT成像恶性肿瘤中HER 3表达的有希望的候选物。本研究的结果表明，该缀合物可用于抗HER 3治疗的患者分层。
Expression of human epidermal growth factor receptor type 3 (HER3) in malignant tumors has been associated with resistance to a variety of anticancer therapies. Several anti-HER3 monoclonal antibodies are currently under pre-clinical and clinical development aiming to overcome HER3-mediated resistance. Radionuclide molecular imaging of HER3 expression may improve treatment by allowing the selection of suitable patients for HER3-targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. In a recent study, we selected affibody molecules with affinity to HER3 at a low picomolar range. The aim of the present study was to develop an anti-HER3 affibody molecule suitable for labeling with radiometals. The HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA HER3-specific affibody molecules were labeled with indium-111 (In-111) and assessed in vitro and in vivo for imaging properties using single photon emission computed tomography (SPECT). Labeling of HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA with In-111 provided stable conjugates. In vitro cell tests demonstrated specific binding of the two conjugates to HER3-expressing BT-474 breast carcinoma cells. In mice bearing BT-474 xenografts, the tumor uptake of the two conjugates was receptor-specific. Direct in vivo comparison of In-111-HEHEHE-Z08698-NOTA and In-111-HEHEHE-Z08699-NOTA demonstrated that the two conjugates provided equal radioactivity uptake in tumors, although the tumor-to-blood ratio was improved for In-111-HEHEHE-Z08698-NOTA [12 +/- 3 vs. 8 +/- 1,4 h post injection (p.i)] due to more efficient blood clearance. In-111-HEHEHE-Z08698-NOTA is a promising candidate for imaging of HER3-expression in malignant tumors using SPECT. Results of the present study indicate that this conjugate could be used for patient stratification for anti-HER3 therapy.