Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer.
Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer.
复制标题
DOI：
10.1073/pnas.2203820119
复制
发表时间：
2022-07-05
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
神经内分泌前列腺癌（NEPC）是前列腺癌的一种高度侵袭性变体，几乎没有有意义的治疗选择。因此，一旦确诊，患者预后不良。NEPC在细胞表面上表达一种称为δ样配体3（DLL 3）的独特蛋白质，该蛋白质在正常细胞的细胞表面上不存在。在本文中，我们开发了一种使用抗DLL 3抗体SC 16的NEPC治疗的分子靶向放射疗法，该抗体用β-发射放射性同位素镥-177（177 Lu）进行放射性标记。177 Lu标记的SC 16在NEPC的皮下异种移植小鼠模型中表现出持久和完全的反应，具有安全的血液学特征。这些数据将有助于临床转化，并为治疗NEPC提供独特的途径。神经内分泌前列腺癌（NEPC）是一种致命的前列腺癌亚型，治疗选择有限。NEPC病变在其细胞表面上独特地表达δ样配体3（DLL 3）。利用DLL 3过表达的优势，我们开发并评估了镥-177（177 Lu）标记的DLL 3靶向抗体SC 16（177 Lu-DTPA-SC 16）作为NEPC的治疗。SC 16用DTPA-CHX-A-螯合剂官能化并用177 Lu放射性标记以产生177 Lu-DTPA-SC 16。使用NCI-H660（NEPC，DLL 3阳性）和DU 145（腺癌，DLL 3阴性）细胞和异种移植物在体外和体内评价177 Lu-DTPA-SC 16的特异性和选择性。在H660和DU 145异种移植荷瘤小鼠中评价了177 Lu-DTPA-SC 16放射性核素疗法的剂量依赖性治疗功效和特异性。通过监测血液学参数评估药物的安全性。177 Lu-DTPA-SC 16在H660异种移植物中显示高肿瘤摄取和特异性，在DU 145异种移植物中具有最小摄取。在所有三种测试剂量的177 Lu-DTPA-SC 16（4.63、9.25和27.75 MBq/小鼠）下，在荷H660小鼠中观察到完全反应; 9.25和27.75 MBq/小鼠剂量是治愈性的。即使是最低的测试剂量也在8只小鼠中的5只（63%）中被证明是有效的，并且复发的肿瘤可以在相同剂量下成功地重新治疗以实现完全缓解。在DU 145异种移植物中，177 Lu-DTPA-SC 16治疗不抑制肿瘤生长。血小板和红细胞压积一过性下降，在2 - 3周达到最低点。这仅在最高剂量队列中超出范围，并在第4周时迅速恢复至正常范围。仅在最高剂量队列中观察到体重减轻。因此，我们的数据表明，177 Lu-DTPA-SC 16是一种有效和安全的放射免疫试剂，用于NEPC患者的检测。
Neuroendocrine prostate cancer (NEPC) is a highly aggressive variant of prostate cancer with few meaningful treatment options. As a result, patients have a poor prognosis once diagnosis is confirmed. NEPC expresses a unique protein called delta-like ligand 3 (DLL3) on the cell surface that is absent on the cell surface of normal cells. Herein, we developed a molecularly targeted radiotherapeutic approach for NEPC treatment using anti-DLL3 antibody SC16 that is radiolabeled with the beta-emitting radioisotope lutetium-177 (177Lu). 177Lu-labeled SC16 demonstrated durable and complete responses in subcutaneous xenograft mouse models of NEPC, with a safe hematologic profile. These data will aid clinical translation and offer a unique avenue for treating NEPC. Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (177Lu)–labeled DLL3-targeting antibody SC16 (177Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with 177Lu to produce 177Lu-DTPA-SC16. Specificity and selectivity of 177Lu-DTPA-SC16 were evaluated in vitro and in vivo using NCI-H660 (NEPC, DLL3-positive) and DU145 (adenocarcinoma, DLL3-negative) cells and xenografts. Dose-dependent treatment efficacy and specificity of 177Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft–bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. 177Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of 177Lu-DTPA-SC16 (4.63, 9.25, and 27.75 MBq/mouse), complete responses were observed in H660-bearing mice; 9.25 and 27.75 MBq/mouse doses were curative. Even the lowest tested dose proved curative in five (63%) of eight mice, and recurring tumors could be successfully re-treated at the same dose to achieve complete responses. In DU145 xenografts, 177Lu-DTPA-SC16 therapy did not inhibit tumor growth. Platelets and hematocrit transiently dropped, reaching nadir at 2 to 3 wk. This was out of range only in the highest-dose cohort and quickly recovered to normal range by week 4. Weight loss was observed only in the highest-dose cohort. Therefore, our data demonstrate that 177Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-21-1533
发表时间：
2022-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Tully KM;Tendler S;Carter LM;Sharma SK;Samuels ZV;Mandleywala K;Korsen JA;Delos Reyes AM;Piersigilli A;Travis WD;Sen T;Pillarsetty N;Poirier JT;Rudin CM;Lewis JS
通讯作者：
Lewis JS
影响因子：
8.8
作者：
Borromeo MD;Savage TK;Kollipara RK;He M;Augustyn A;Osborne JK;Girard L;Minna JD;Gazdar AF;Cobb MH;Johnson JE
通讯作者：
Johnson JE
DOI：
10.1083/jcb.200702009
发表时间：
2007-07-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Geffers I;Serth K;Chapman G;Jaekel R;Schuster-Gossler K;Cordes R;Sparrow DB;Kremmer E;Dunwoodie SL;Klein T;Gossler A
通讯作者：
Gossler A
影响因子：
17.1
作者：
Puca, Loredana;Gavyert, Katie;Beltran, Himisha
通讯作者：
Beltran, Himisha
DOI：
10.1158/1078-0432.ccr-18-1278
发表时间：
2019-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Koshkin VS;Garcia JA;Reynolds J;Elson P;Magi-Galluzzi C;McKenney JK;Isse K;Bishop E;Saunders LR;Balyimez A;Rashid S;Hu M;Stephenson AJ;Fergany AF;Lee BH;Haber GP;Dowlati A;Gilligan T;Ornstein MC;Rini BI;Abazeed ME;Mian OY;Grivas P
通讯作者：
Grivas P