A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy.
A Self-Assembling and Disassembling (SADA) Bispecific Antibody (BsAb) Platform for Curative Two-step Pretargeted Radioimmunotherapy.
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用于治疗性两步预靶向放射免疫治疗的自组装和拆卸 (SADA) 双特异性抗体 (BsAb) 平台。
DOI：
10.1158/1078-0432.ccr-20-2150
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发表时间：
2021-01-15
期刊：
影响因子：
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通讯作者：
Cheung NK
中科院分区：
文献类型：
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作者：
Santich BH;Cheal SM;Ahmed M;McDevitt MR;Ouerfelli O;Yang G;Veach DR;Fung EK;Patel M;Burnes Vargas D;Malik AA;Guo HF;Zanzonico PB;Monette S;Michel AO;Rudin CM;Larson SM;Cheung NK
由于治疗指数(TI)较低，许多癌症治疗方法存在对重要器官的剂量限制毒性。为了克服这些挑战，我们开发了一种新的多聚体平台，可以快速从血液中去除肿瘤靶向蛋白，从而显著提高TI。该平台被设计为将自组装和解离(SADA)结构域与串联单链双特异性抗体(BsAb，抗神经节苷脂GD2 x抗DOTA)融合。使用两步预靶向放射免疫治疗(PRIT)的多种体内肿瘤模型评估SADA-BsAbs，以评估肿瘤摄取、剂量学和抗肿瘤反应。SADA-BsAbs自组装成稳定的四聚体(220 KDa)，但也可以分解成二聚体或单体(55 KDa)，通过肾滤过迅速清除，大大降低小鼠的免疫原性。当与快速清除DOTA笼中的PET同位素一起使用时，SADA-BsAbs显示出准确的肿瘤定位、剂量测定和改进的PET/CT成像对比度。当与治疗性同位素结合时，两步SADA-PRIT安全地将大剂量的阿尔法发射(225Ac，1.48MBq/kg)或贝塔发射(177Lu，6660MBq/kg)DOTA有效载荷输送到肿瘤，消融它们，对骨髓、肾脏或肝脏没有任何短期或长期毒性。SADA-BsAb平台安全地将大剂量放射性同位素输送到肿瘤，对骨髓、肾脏或肝脏没有毒性。由于其模块化，SADA-BsAbs可以很容易地适应大多数肿瘤抗原、肿瘤类型或药物传递途径，以提高TI和最大限度地增加传递剂量。
Many cancer treatments suffer from dose-limiting toxicities to vital organs due to poor therapeutic indices (TI). To overcome these challenges we developed a novel multimerization platform that rapidly removed tumor targeting proteins from the blood to substantially improve TI. The platform was designed as a fusion of a Self-Assembling and DisAssembling (SADA) domain to a tandem single-chain bispecific antibody (BsAb, anti-ganglioside GD2 x anti-DOTA). SADA-BsAbs were assessed with multiple in vivo tumor models using 2-step pretargeted radioimmunotherapy (PRIT) to evaluate tumor uptake, dosimetry and anti-tumor responses. SADA-BsAbs self-assembled into stable tetramers (220 kDa) but could also disassemble into dimers or monomers (55 kDa) that rapidly cleared via renal filtration and substantially reduced immunogenicity in mice. When used with rapidly clearing DOTA-caged PET isotopes, SADA-BsAbs demonstrated accurate tumor localization, dosimetry, and improved imaging contrast by PET/CT. When combined with therapeutic isotopes, 2-step SADA-PRIT safely delivered massive doses of alpha-emitting (225Ac, 1.48 MBq/kg) or beta-emitting (177Lu, 6,660 MBq/kg) DOTA payloads to tumors, ablating them without any short-term or long-term toxicities to the bone marrow, kidneys, or liver. The SADA-BsAb platform safely delivered large doses of radioisotopes to tumors and demonstrated no toxicities to the bone marrow, kidneys or liver. Due to its modularity, SADA-BsAbs can be easily adapted to most tumor antigens, tumor types, or drug delivery approaches to improve TI and maximize the delivered dose.