Clinical development of a DLL3-targeted theranostic for small cell lung cancer

项目摘要 小细胞肺癌（SCLC）具有极高的转移潜力，最初的稳定性， 对DNA损伤剂的反应，以及几乎普遍的耐药性发展。的这种组合 获得性治疗耐药-通常表现为对肿瘤的交叉耐药， 多种药物-强调了对通过新机制操作的新全身疗法的迫切需求 以改善患者的治疗效果。 δ样配体3（DLL 3）最近被鉴定为SCLC的治疗靶点。高度 该蛋白质的肿瘤选择性表面表达使其成为抗体药物的极好候选靶点 偶联物（ADC）。Rovalpituzumab tesserine（Rova-T）是一种显示出令人鼓舞的疗效的ADC 信号在诊所然而，尽管有明显的临床益处，但这种药物也与一些 可归因于蒽环类PBD弹头的存在的严重不良事件。DLL 3靶向 这些方法需要实时、定量诊断生物标志物和治疗方法， 降低毒性。 我们提出了一种治疗诊断方法，包括89 Zr免疫PET和90 Y/177 Lu 放射免疫第一个目标改进了已经有前途的生物缀合化学。我们 已经能够获得高对比度的免疫PET图像使用非特异性胺标记和位点特异性 马来酰亚胺生物缀合。我们将通过开发更稳定的巯基点击来改进这种方法。 89 Zr和90 Y/177 Lu的甲基砜螯合剂，以最大限度地减少肾脏剂量。第二个目标是确定临床前 给药参数，并全面优化传统细胞系异种移植物的功效和毒性。我们 初步的成像数据集中在H82上，H82是一种来源于化疗患者的SCLC细胞系。这 细胞系在体外和体内对依托泊苷具有很强的抗性，并将用于鉴定 在体内显示功效，同时使对肾脏的剂量最小化。不同的剂量范围和时间表将是 探讨了最后一个目的是探讨放射治疗在各种体内环境，包括病变大小范围从 0.1直径为10 mm，代表化疗无效和化疗耐药疾病。放射性同位素具有 不同的能量沉积取决于靶向肿瘤的体积。我们将评估90 Y， 177 Lu放射性同位素在不同的小细胞肺癌体内模型中根除肺癌病灶的能力 不同的尺寸。实验室中的一个独特资源是我们收集的10对化疗无效和化疗耐药的 患者来源的异种移植物系。我们将特别强调在以下背景下建立效力： 获得性耐药性 本研究中获得的数据应提供临床前证据，以支持 基于罗伐匹妥珠单抗的DLL 3靶向治疗诊断剂。

PROJECT SUMMARY Small cell lung cancer (SCLC) is remarkable for exceptionally high metastatic potential, initial robust response to DNA damaging agents, and near universal development of resistance. This combination of predilection for early metastasis acquired treatment resistance – often times manifested as cross resistance to multiple agents – highlights a critical need for novel systemic therapies operating through a novel mechanism in order to achieve improved patient outcomes. Delta-like ligand 3 (DLL3), has recently been identified as a therapeutic target in SCLC. The highly tumor-selective surface expression of this protein make it an excellent candidate target for an antibody drug conjugate (ADC). Rovalpituzumab tesserine (Rova-T) is one such ADC that is showing encouraging efficacy signals in the clinic. However, despite apparent clinical benefit, this agent has also been associated with some severe adverse events attributable to the presence of the anthracycline PBD warhead. DLL3 targeting approaches are in need of both a real-time, quantitative diagnostic biomarker and a therapeutic approach with reduced toxicity. We propose a theranostic approach comprising on 89Zr immunoPET and a 90Y/177Lu radioimmunotherapeutic. The first Aim improves upon already promising bioconjugation chemistry. We are already able to obtain high-contrast immunoPET images using non-specific amine labeling and site-specific maleimide bioconjugation. We will improve upon this approach by developing more stable thiol-clickable methylsuflone chelators for 89Zr and 90Y/177Lu to minimize kidney dose. The second Aim identifies preclinical dosing parameters and comprehensively optimizes efficacy and toxicity in a traditional cell line xenograft. Our preliminary imaging data is focused on H82, an SCLC cell lined derived from a chemoexperienced patient. This cell line is very resistant to etoposide in vitro and in vivo and will be used to identify a radiotherapy dose that demonstrates efficacy in vivo, while minimizing dose to the kidney. Different dose ranges and schedules will be explored. The final Aim explores radiotherapy in a variety of in vivo contexts including lesion sizes ranging from 0.1 to 10 mm in diameter and representing both chemonaïve and chemoresistant disease. Radioisotopes have different energy deposition depending on the volume of the tumor being targeted. We will evaluate 90Y and 177Lu radioisotopes in different in vivo models of small cell lung cancer for the ability to eradicate lesions of different sizes. A unique resource in the lab is our collection of 10 paired chemonaïve and chemoresistant patient-derived xenograft lines. We will place particular emphasis on establishing efficacy in the context of acquired chemoresistance. Data obtained in this study should provide preclinical evidence in support of clinical translation of a DLL3 targeting theranostic based on rovalpituzumab.