Visualizing Galectin-3 Binding Protein Expression with ImmunoPET.
Visualizing Galectin-3 Binding Protein Expression with ImmunoPET.
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DOI：
10.1021/acs.molpharmaceut.3c00241
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发表时间：
2023-06-05
影响因子：
4.9
通讯作者：
Zeglis BM
中科院分区：
文献类型：
--
作者：
Keinänen O;Sarrett SM;Delaney S;Rodriguez C;Dayts EJ;Capone E;Sauniere F;Ippoliti R;Sala G;Iacobelli S;Zeglis BM
Galectin-3 结合蛋白 (Gal-3BP) 是一种糖蛋白，在多种癌症中过度表达和分泌，并且被认为是黑色素瘤、非小细胞肺癌、头颈鳞状细胞癌和乳腺癌肿瘤进展和不良预后的标志物。 Gal-3BP 在多种肿瘤中的表达使其成为诊断和治疗的诱人靶标，包括免疫正电子发射断层扫描 (immunoPET) 探针和抗体药物偶联物 (ADC)。在此，我们报告了一对用于 89Zr-immunoPET 的 Gal-3BP 靶向放射免疫缀合物的开发、体外表征和体内评估。人源化抗 Gal-3BP 抗体（1959）及其相应的 ADC 1959-sss/DM4（DM4 = ravtansine）用去铁胺 (DFO) 进行修饰，产生带有 1-2 DFO/单克隆抗体的 DFO-1959 和 DFO-1959-sss/DM4 免疫缀合物。在酶联免疫吸附测定实验中，两种 DFO 修饰的免疫缀合物保留了对 Gal-3BP 的亲和力。带有螯合剂的抗体用锆 89 (t1/2 ≈ 3.3 d) 进行放射性标记，产生放射免疫缀合物 - [89Zr]Zr-DFO-1959 和 [89Zr]Zr-DFO-1959-sss/DM4 - 具有高比活性 (>444 MBq/mg，>12 mCi/mg) 和稳定性 (>80% 完整后) 37°C 人血清中 168 小时）。在皮下分泌 Gal-3BP 的 A375-MA1 异种移植物的小鼠中，[89Zr]Zr-DFO-1959 清晰地描绘了肿瘤组织，在注射后 120 小时达到最大肿瘤活性浓度 (54.8 ± 15.8%ID/g) 和肿瘤与背景对比度 (肿瘤与血液 = 8.0 ± 4.6)。对携带皮下表达 Gal-3BP 的黑色素瘤患者来源的异种移植物的小鼠施用 [89Zr]Zr-DFO-1959 产生了类似的有希望的结果。 [89Zr]Zr-DFO-1959 和 [89Zr]Zr-DFO-1959-sss/DM4 在携带 A375-MA1 肿瘤的小鼠中表现出几乎相同的药代动力学特征，尽管后者在脾脏和肾脏中产生更高的摄取。 [89Zr]Zr-DFO-1959 和 [89Zr]Zr-DFO-1959-sss/DM4 均能有效地使黑色素瘤小鼠模型中分泌 Gal-3BP 的肿瘤可视化。这些结果表明，这两种探针都可以在表达 Gal-3BP 的恶性肿瘤的临床成像中发挥作用，特别是作为伴随治疗诊断来识别可能对 Gal-3BP 靶向治疗（如 1959-sss/DM4）有反应的患者。
Galectin-3 binding protein (Gal-3BP) is a glycoprotein that is overexpressed and secreted by several cancers and has been implicated as a marker of both tumor progression and poor prognosis in melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and breast cancer. The expression of Gal-3BP by a variety of neoplasms makes it an enticing target for both diagnostics and therapeutics, including immuno-positron emission tomography (immunoPET) probes and antibody-drug conjugates (ADCs). Herein, we report the development, in vitro characterization, and in vivo evaluation of a pair of Gal-3BP-targeting radioimmunoconjugates for 89Zr-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its corresponding ADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine (DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing 1–2 DFO/monoclonal antibody. Both DFO-modified immunoconjugates retained their affinity for Gal-3BP in enzyme-linked immunosorbent assay experiments. The chelator-bearing antibodies were radiolabeled with zirconium-89 (t1/2 ≈ 3.3 d) to produce radioimmunoconjugates — [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 — with high specific activity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intact after 168 h in human serum at 37 °C). In mice bearing subcutaneous Gal-3BP-secreting A375-MA1 xenografts, [89Zr]Zr-DFO-1959 clearly delineated tumor tissue, reaching a maximum tumoral activity concentration (54.8 ± 15.8%ID/g) and tumor-to-background contrast (tumor-to-blood = 8.0 ± 4.6) at 120 h post-injection. The administration of [89Zr]Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressing melanoma patient-derived xenografts produced similarly promising results. [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 exhibited nearly identical pharmacokinetic profiles in the mice bearing A375-MA1 tumors, though the latter produced higher uptake in the spleen and kidneys. Both [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 effectively visualized Gal-3BP-secreting tumors in murine models of melanoma. These results suggest that both probes could play a role in the clinical imaging of Gal-3BP-expressing malignancies, particularly as companion theranostics for the identification of patients likely to respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.
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DOI：
10.1016/j.jconrel.2017.08.040
发表时间：
2017-10-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Dal Corso A;Gébleux R;Murer P;Soltermann A;Neri D
通讯作者：
Neri D
影响因子：
10.8
作者：
Giansanti, Francesco;Capone, Emily;Iacobelli, Stefano
通讯作者：
Iacobelli, Stefano
影响因子：
4.4
作者：
Mariscal, Javier;Fernandez-Puente, Patricia;Abal, Miguel
通讯作者：
Abal, Miguel
影响因子：
4.7
作者：
Piccolo, Enza;Tinari, Nicola;Iacobelli, Stefano
通讯作者：
Iacobelli, Stefano
影响因子：
4.9
作者：
Adumeau P;Vivier D;Sharma SK;Wang J;Zhang T;Chen A;Agnew BJ;Zeglis BM
通讯作者：
Zeglis BM