Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity.
Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity.
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DOI：
10.1158/1078-0432.ccr-21-1533
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发表时间：
2022-04-01
期刊：
影响因子：
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通讯作者：
Lewis JS
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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
小细胞肺癌是一种非常致命的肺癌，治疗选择有限。δ样配体3（DLL 3）是一个有吸引力的治疗靶点，因为表面表达几乎仅限于肿瘤细胞。我们用治疗性放射性同位素镥-177放射性标记抗DLL 3单克隆抗体SC 16。[177 Lu]Lu-DTPA-CHX-A”-SC 16结合SCLC细胞上的DLL 3，并提供靶向放射治疗，同时最大限度地减少对健康组织的辐射。[177 Lu]Lu-DTPA-CHX-A”-SC 16在肿瘤异种移植物中表现出具有DLL 3靶特异性的高肿瘤摄取。生物分布研究的剂量测定分析表明，血液和肝脏最有可能因高剂量[177 Lu]Lu-DTPA-CHX-A”-SC 16给药而产生毒性。在放射抗性NCI-H82模型中，存活研究表明，500 μCi和750 μCi剂量的[177 Lu]Lu-DTPA-CHX-A”-SC 16导致存活时间延长，接受高剂量[177 Lu]Lu-DTPA-CHX-A”-SC 16的8只小鼠中有3只具有病理学证实的完全缓解。在患者来源的异种移植物模型Lu 149中，所有剂量的[177 Lu]Lu-DTPA-CHX-A”-SC 16均显著延长存活。在250 μCi和500 μCi剂量下，分别有5/10和7/9只小鼠表现出病理学证实的完全缓解。接受750 μCi [177 Lu]Lu-DTPA-CHX-A”-SC 16的10只小鼠中有4只表现出严重到足以实施安乐死的瘀点，但其余6只小鼠表现出病理学证实的完全反应。对来自部分应答的残留组织进行的IHC证实了保留的DLL 3表达。血液学毒性呈剂量依赖性和一过性，4周内完全恢复。未观察到肝毒性。总之，令人信服的抗肿瘤功效、病理学完全响应以及轻度和短暂的毒性特征证明了[177 Lu]Lu-DTPA-CHX-A”-SC 16的临床转化的强大潜力。
Small cell lung cancer is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells. We radiolabeled the anti-DLL3 monoclonal antibody SC16 with the therapeutic radioisotope, Lutetium-177. [177Lu]Lu-DTPA-CHX-A”-SC16 binds to DLL3 on SCLC cells and delivers targeted radiotherapy while minimizing radiation to healthy tissue. [177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated high tumor uptake with DLL3-target specificity in tumor xenografts. Dosimetry analyses of biodistribution studies suggested that the blood and liver were most at risk for toxicity from treatment with high doses of [177Lu]Lu-DTPA-CHX-A”-SC16. In the radioresistant NCI-H82 model, survival studies showed that 500 μCi and 750 μCi doses of [177Lu]Lu-DTPA-CHX-A”-SC16 led to prolonged survival over controls, and three of the eight mice that received high doses of [177Lu]Lu-DTPA-CHX-A”-SC16 had pathologically confirmed complete responses. In the patient-derived xenograft model Lu149, all doses of [177Lu]Lu-DTPA-CHX-A”-SC16 markedly prolonged survival. At the 250 μCi and 500 μCi doses, 5/10 and 7/9 mice demonstrated pathologically confirmed complete responses, respectively. Four of ten mice that received 750 μCi of [177Lu]Lu-DTPA-CHX-A”-SC16 demonstrated petechiae severe enough to warrant euthanasia, but the remaining six mice demonstrated pathologically confirmed complete responses. IHC on residual tissues from partial responses confirmed retained DLL3 expression. Hematologic toxicity was dose-dependent and transient, with full recovery within 4 weeks. Hepatotoxicity was not observed. Together, the compelling antitumor efficacy, pathologic complete responses, and mild and transient toxicity profile demonstrate strong potential for clinical translation of [177Lu]Lu-DTPA-CHX-A”-SC16.