Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity ⁸⁶Y- or ¹⁷⁷Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates.
Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity ⁸⁶Y- or ¹⁷⁷Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates.
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DOI：
10.1007/s00259-015-3254-8
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发表时间：
2016-05
影响因子：
9.1
通讯作者：
Larson SM
中科院分区：
文献类型：
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作者：
Cheal SM;Xu H;Guo HF;Lee SG;Punzalan B;Chalasani S;Fung EK;Jungbluth A;Zanzonico PB;Carrasquillo JA;O'Donoghue J;Smith-Jones PM;Wittrup KD;Cheung NV;Larson SM
GPA33是一种结直肠癌（CRC）抗原，在hua33介导的肿瘤靶向后具有独特的保留特性。我们测试了一种针对CRC的预靶向放射免疫治疗（PRIT）方法，该方法使用了一种四价双特异性抗体，该抗体对GPA33肿瘤抗原和DOTA-Bn（放射性镧系金属）复合物具有双重特异性。通过连续静脉滴注huA33-C825、葡聚糖基清除剂（CA）和c825半抗原177lu -或86Y-DOTA-Bn，在SW1222皮下注射小鼠体内优化PRIT。CRC异种移植模型。利用优化后的PRIT，获得73（肿瘤/血液）和12（肿瘤/肾脏）肿瘤辐射吸收剂量的治疗指标（TIs）。单周期PRIT对肿瘤、血液、肝脏、脾脏和肾脏的估计吸收剂量（cGy/MBq）分别为65.8、0.9 （TI: 73）、6.3 （TI: 10）、6.6 （TI: 10）和5.3 （TI: 12）。PRIT治疗的两个周期（66.6或111 MBq - 177Lu-DOTA-Bn）是安全有效的，在已建立的s.c.肿瘤（100-700 mm3）中有9/9完全缓解，2/9在140天内没有复发。该模型中肿瘤的log kill估计为2.1-3.0基于500-mm3肿瘤复发的时间。此外，通过正电子发射dota半抗原86Y-DOTA-Bn的PET成像进行PRIT剂量测定/诊断。我们已经开发了抗gpa33 PRIT，作为一种三步治疗策略，用于临床前检测，剂量测定和安全靶向放疗已建立的人类结直肠小鼠异种移植。
GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pre-targeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn (radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent (CA), and the C825-haptens 177Lu-or 86Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI: 73), 6.3 (TI: 10), 6.6 (TI: 10), and 5.3 (TI: 12), respectively. Two cycles of PRIT treatment (66.6 or 111 MBq 177Lu-DOTA-Bn) were safe and effective, with 9/9 complete responses of established s.c. tumors (100–700 mm3) and 2/9 alive without recurrence >140 d. Tumor log kill in this model was estimated to be 2.1–3.0 based time to 500-mm3 tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA-hapten 86Y-DOTA-Bn. We have developed anti-GPA33 PRIT, as a triple-step theranostic strategy for pre-clinical detection, dosimetry and safe targeted radiotherapy of established human colorectal mouse xenografts.