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,Molecular Pharmaceutics

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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
Molecular Pharmaceutics ( IF 4.9 ) 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,

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Affiliation

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，在体外和体内两种前途每个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。

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Evaluating 225Ac and 177Lu Radioimmunoconjugates against Antibody–Drug Conjugates for Small-Cell Lung Cancer

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.

更新日期：2020-11-02

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