Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. We conducted an open-label, first-in-human study of immunoPET-CT imaging with [Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0–2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37–74 MBq [Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3–6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with , . Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23–81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3–6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

中文翻译：

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使用 [89Zr]Zr-DFO-SC16.56 抗 DLL3 抗体对肺和前列腺高级神经内分泌肿瘤患者进行成像：1/2 期首次人体试验


Delta 样配体 3 (DLL3) 在小细胞肺癌 (SCLC) 和神经内分泌前列腺癌细胞表面异常表达。我们评估了 DLL3 靶向成像示踪剂 [Zr]Zr-DFO-SC16.56（由与 p-SCN-Bn-去铁胺 [DFO] 缀合的抗 DLL3 抗体 SC16.56 组成，作为螯合剂）的安全性和可行性锆89）用于神经内分泌源性癌症患者。我们使用 [Zr]Zr-DFO-SC16.56 进行了一项开放标签、首次人体免疫 PET-CT 成像研究。该研究是在美国纽约市纪念斯隆凯特琳癌症中心进行的。年龄 18 岁或以上、经组织学证实患有神经内分泌源性恶性肿瘤且东部肿瘤合作组表现状态为 0-2 的患者符合资格。 SCLC 患者的初始队列（队列 1）接受 37–74 MBq [Zr]Zr-DFO-SC16.56 作为单次静脉输注，总质量剂量为 2·5 mg，并在 1 时进行连续 PET-CT 扫描。 h，注射后第1天、第3天和第7天。该研究第 1 阶段（队列 1）的主要结果是估计终末清除半衰期，确定整个器官时间积分活动系数，并评估 [Zr]Zr-DFO-SC16.56 的安全性。由其他患者组成的扩展队列（患有 SCLC、神经内分泌前列腺癌、非典型类癌肿瘤和非小细胞肺癌；队列 2）以相同的活性接受单次 [Zr]Zr-DFO-SC16.56 输注，并且与初始队列一样接受大量剂量，然后 3-6 天后进行一次 PET-CT 扫描。通过免疫组织化学评估回顾性收集的肿瘤活检样本中的 DLL3。 第 2 组研究的第 2 阶段的主要结果是确定肿瘤摄取示踪剂与肿瘤内 DLL3 蛋白表达之间的潜在关联（通过免疫组织化学测定）。这项研究正在进行中，并已在 , 注册。 2020年2月11日至2023年1月30日期间，有12名男性（67%）和6名女性（33%）入组，中位年龄为64岁（范围23-81岁）。第 1 组包括 3 名患者，第 2 组包括另外 15 名患者。第 1 组中 3 名 SCLC 患者的影像显示，在注射后第 3 天和第 7 天，[Zr]Zr-DFO-SC16.56 具有强烈的肿瘤特异性摄取。血清清除率为双相，估计终末清除半衰期为 119 小时 (SD 31)。肝脏平均吸收剂量最高（1·83 mGy/MBq [SD 0·36]），平均有效剂量为0·49 mSv/MBq（SD 0·10）。在队列 2 中，给药后第 3-6 天的单次免疫 PET-CT 扫描可以在 15 名患者中的 12 名 (80%) 中描绘出 DLL3 亲和的肿瘤。肿瘤摄取在患者之间、患者内部以及解剖部位之间存在差异，最大标准化摄取值范围很广（从 3·3 到 66·7）。在具有可评估组织的 16 名患者中，有 15 名患者 (94%) 的 [Zr]Zr-DFO-SC16.56 肿瘤摄取与 DLL3 免疫组织化学一致。 PET 扫描显示两名非活跃 DLL3 SCLC 和神经内分泌前列腺癌患者的肿瘤免疫组织化学显示 DLL3 表达最低。 18 名患者中有 1 名（6%）出现 1 级过敏反应；两组中均未发现 2 级或更严重的不良事件。 DLL3 PET-CT对神经内分泌癌患者进行成像是安全可行的。这些结果显示了 [Zr]Zr-DFO-SC16.56 对于表达 DLL3 的恶性肿瘤的非侵入性体内检测的潜在用途。 美国国立卫生研究院、前列腺癌基金会和斯坎内尔基金会。