Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia.
Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia.
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DOI：
10.1021/acscombsci.0c00081
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发表时间：
2020-10-12
影响因子：
--
通讯作者：
Dreaden EC
中科院分区：
文献类型：
--
作者：
Do P;Perdue LA;Chyong A;Hunter R;Dougan J;Henry CJ;Porter CC;Dreaden EC
与免疫细胞结合并将其细胞毒性活性重定向到病变细胞的疗法代表了应用于癌症、狼疮和其他疾病的免疫疗法的有前途和通用的方法;然而，用于发现这些疗法的传统方法通常是时间密集型的，并且缺乏相关的基于靶点的发现方法的通量。受细胞因子IL-12可增强临床批准的T细胞重定向治疗Blinatumomab的抗白血病活性这一观察结果的启发，我们在此描述了嵌合免疫细胞重定向剂的结构和组装，该试剂可将原代人T细胞的裂解活性重定向至白血病B细胞，同时共靶向T细胞刺激性IL-12的递送。我们进一步描述了一种新的方法，用于平行组装这些双特异性T细胞接合细胞因子（BiTE因子）的组成多样的文库及其高通量表型筛选，仅需要几天的时间进行命中鉴定和组成-功能关系的分析。使用这种方法，我们鉴定了CD 19 × CD 3 × IL 12化合物，其表现出与目前FDA批准的白血病疗法相当的体外溶解活性，以及与特定细胞-细胞接触、细胞因子递送和白血病细胞溶解相关的药物治疗。考虑到这些多价化合物的模块化性质及其快速组装/筛选，我们预计这种治疗方法在未来可以轻松扩展到广泛的免疫细胞，病变细胞和可溶性蛋白质组合。
Therapies that bind with immune cells and redirect their cytotoxic activity toward diseased cells represent a promising and versatile approach to immunotherapy with applications in cancer, lupus, and other diseases; traditional methods for discovering these therapies, however, are often time-intensive and lack the throughput of related target-based discovery approaches. Inspired by the observation that the cytokine, IL-12, can enhance antileukemic activity of the clinically approved T cell redirecting therapy, blinatumomab, here we describe the structure and assembly of a chimeric immune cell-redirecting agent which redirects the lytic activity of primary human T cells toward leukemic B cells and simultaneously cotargets the delivery of T cell-stimulating IL-12. We further describe a novel method for the parallel assembly of compositionally diverse libraries of these bispecific T cell engaging cytokines (BiTEokines) and their high-throughput phenotypic screening, requiring just days for hit identification and the analysis of composition-function relationships. Using this approach, we identified CD19 × CD3 × IL12 compounds that exhibit ex vivo lytic activity comparable to current FDA-approved therapies for leukemia and correlated drug treatment with specific cell–cell contact, cytokine delivery, and leukemia cell lysis. Given the modular nature of these multivalent compounds and their rapid assembly/screening, we anticipate facile extension of this therapeutic approach to a wide range of immune cells, diseased cells, and soluble protein combinations in the future.
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影响因子：
10.1
作者：
Frankel, Arthur E.;Woo, Jung H.;Neville, David M.
通讯作者：
Neville, David M.
泰勒分散分析与动态光散射相比，用于治疗性肽和蛋白质及其聚集体的尺寸分析。
影响因子：
3.7
作者：
Hawe, Andrea;Hulse, Wendy L.;Jiskoot, Wim;Forbes, Robert T.
通讯作者：
Forbes, Robert T.
DOI：
10.1056/nejmoa1609783
发表时间：
2017-03-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kantarjian H;Stein A;Gökbuget N;Fielding AK;Schuh AC;Ribera JM;Wei A;Dombret H;Foà R;Bassan R;Arslan Ö;Sanz MA;Bergeron J;Demirkan F;Lech-Maranda E;Rambaldi A;Thomas X;Horst HA;Brüggemann M;Klapper W;Wood BL;Fleishman A;Nagorsen D;Holland C;Zimmerman Z;Topp MS
通讯作者：
Topp MS
影响因子：
32.4
作者：
Minguet, Susana;Swamy, Mahima;Schamel, Wolfgang W. A.
通讯作者：
Schamel, Wolfgang W. A.
影响因子：
7.2
作者：
Braun, Matthias;Ress, Marie L.;Woelfl, Matthias
通讯作者：
Woelfl, Matthias