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Evaluating 225Ac and 177Lu Radioimmunoconjugates against Antibody–Drug Conjugates for Small-Cell Lung Cancer
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-10-12 , DOI: 10.1021/acs.molpharmaceut.0c00703
Andrew L Lakes 1 , Dahlia D An 1 , Stacey S Gauny 1 , Camille Ansoborlo 1 , Benjamin H Liang 1 , Julian A Rees 1 , Kristen D McKnight 2 , Holger Karsunky 2 , Rebecca J Abergel 1, 3
Affiliation  

Interest in the use of 225Ac for targeted alpha therapies has increased dramatically over the past few years, resulting in a multitude of new isotope production and translational research efforts. However, 225Ac radioimmunoconjugate (RIC) research is still in its infancy, with most prior experience in hematologic malignancies and only one reported preclinical solid tumor study using 225Ac RICs. In an effort to compare 225Ac RICs to other current antibody conjugates, a variety of RICs are tested against intractable small-cell lung cancer (SCLC). We directly compare, in vitro and in vivo, two promising candidates of each α or β category, 225Ac and 177Lu, versus pyrrolobenzodiazepine (PBD) nonradioactive benchmarks. The monoclonal antibody constructs are targeted to either delta like 3 protein (DLL3), a recently discovered SCLC target, or CD46 as a positive control. An immunocompromised maximum tolerated dose assay is performed on NOD SCID mice, along with tumor efficacy proof-of-concept studies in vivo. We overview the conjugation techniques required to create serum-stable RICs and characterize and compare in vitro cell killing with RICs conjugated to nonspecific antibodies (huIgG1) with either native or site-specific thiol loci against tumor antigen DLL3-expressing and nonexpressing cell lines. Using patient-derived xenografts of SCLC onto NOD SCID mice, solid tumor growth was controlled throughout 3 weeks before growth appeared, in comparison to PBD conjugate controls. NOD SCID mice showed lengthened survival using 225Ac compared to 177Lu RICs, and PBD dimers showed full tumor suppression with nine out of ten mice. The exploration of RICs on a variety of antibody–antigen systems is necessary to direct efforts in cancer research toward promising candidates. However, the anti-DLL3-RIC system with 225Ac and 177Lu appears to be not as effective as the anti-DLL3-PBD counterpart in SCLC therapy with matched antibodies and portrays the challenges in both SCLC therapy as well as the specialized utility of RICs in cancer treatment.

中文翻译:

评估 225Ac 和 177Lu 放射免疫偶联物对抗小细胞肺癌的抗体药物偶联物

在过去几年中,人们对使用225 Ac 进行靶向 α 疗法的兴趣急剧增加,从而产生了大量新的同位素生产和转化研究工作。然而,225 Ac 放射免疫偶联物 (RIC) 的研究仍处于起步阶段,在血液系统恶性肿瘤方面的经验最多,只有一项报告了使用225 Ac RIC 的临床前实体瘤研究。为了将225 Ac RIC 与其他当前的抗体偶联物进行比较,针对难治性小细胞肺癌 (SCLC) 测试了多种 RIC。我们直接比较,在体外体内两种前途每个α或β的候选人-类,225Ac 和177 Lu,与吡咯并苯二氮卓 (PBD) 非放射性基准。单克隆抗体构建体靶向最近发现的 SCLC 靶标 delta 样 3 蛋白 (DLL3) 或作为阳性对照的 CD46。耐受剂量测定法免疫受损的最大值上NOD SCID小鼠进行的,与证明的概念肿瘤效力研究沿着体内。我们概述了创建血清稳定 RIC 所需的结合技术,并在体外进行表征和比较使用与非特异性抗体 (huIgG1) 偶联的 RIC 杀死细胞,该抗体具有针对肿瘤抗原 DLL3 表达和非表达细胞系的天然或位点特异性硫醇位点。使用患者来源的 SCLC 异种移植物移植到 NOD SCID 小鼠上,与 PBD 偶联物对照相比,实体瘤的生长在出现生长之前的 3 周内得到控制。与使用177 Lu RIC相比,使用225 Ac 的NOD SCID 小鼠显示出更长的生存期,并且 PBD 二聚体显示出十分之九的肿瘤抑制。在各种抗体 - 抗原系统上探索 RIC 对于将癌症研究的努力指向有希望的候选者来说是必要的。然而,具有225 Ac 和177在使用匹配抗体的 SCLC 治疗中,Lu 似乎不如抗 DLL3-PBD 对应物有效,并且描绘了 SCLC 治疗以及 RIC 在癌症治疗中的专门用途所面临的挑战。
更新日期:2020-11-02
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