Development and Characterization of Nanobody-Derived CD47 Theranostic Pairs in Solid Tumors.
Development and Characterization of Nanobody-Derived CD47 Theranostic Pairs in Solid Tumors.
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DOI：
10.34133/research.0077
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Zhang Y;Zhang D;An S;Liu Q;Liang C;Li J;Liu P;Wu C;Huang G;Wei W;Liu J
CD 47的过表达常见于各种类型的人类恶性肿瘤，抑制骨髓介导的肿瘤细胞清除，影响癌症患者的预后。通过绘制生物标志物表达，免疫正电子发射断层扫描已越来越多地用于患者筛查和反应监测。通过用重组人CD 47免疫羊驼，我们制备了靶向CD 47的纳米抗体C2并开发了[68 Ga]Ga-NOTA-C2，随后探索了在表达CD 47的肿瘤模型（包括胃癌患者来源的异种移植物模型）中的诊断价值。通过将C2与白蛋白结合结构域（ABD）融合，我们合成了ABDC 2，其具有增加的体内半衰期和改善的靶向性质。我们进一步用68 Ga/89 Zr/177 Lu标记ABDC 2以开发放射性核素治疗诊断对，并在细胞和患者来源的模型中评估药物的药代动力学和治疗诊断功效。C2和ABDC 2均与人CD 47特异性反应，KD值分别为23.50和84.57 pM。[68 Ga]Ga-NOTA-C2的开发具有高放射化学纯度（99 >%，n = 4），并且肿瘤中的CD 47表达可视化。与[68 Ga]Ga-NOTA-C2的快速肾清除和短半衰期相比，[68 Ga]Ga-NOTA-ABDC 2和[89 Zr]Zr-DFO-ABDC 2均显示出延长的循环和增加的肿瘤摄取，其中[89 Zr]Zr-DFO-ABDC 2的最高摄取发生在注射后72小时。此外，[177 Lu]Lu-DOTA-ABDC 2放射免疫治疗抑制了肿瘤生长，但与毒性相关，从而阻碍了治疗方案的进一步优化。总之，我们报道了一系列纳米抗体衍生的CD 47靶向剂，其中[68 Ga]Ga-NOTA-C2和[89 Zr]Zr-DFO-ABDC 2是容易翻译的。CD 47靶向治疗诊断对的优化和翻译可能为CD 47靶向治疗实体瘤提供新的前景。
Overexpression of CD47 is frequently observed in various types of human malignancies, inhibiting myeloid-mediated elimination of tumor cells and affecting the prognosis of cancer patients. By mapping biomarker expression, immuno-positron emission tomography has been increasingly used for patient screening and response monitoring. By immunization alpacas with recombinant human CD47, we prepared a CD47-targeting nanobody C2 and developed [68Ga]Ga-NOTA-C2, followed by an exploration of the diagnostic value in CD47-expressing tumor models including gastric-cancer patient-derived xenograft models. By fusing C2 to an albumin binding domain (ABD), we synthesized ABDC2, which had increased in vivo half-life and improved targeting properties. We further labeled ABDC2 with 68Ga/89Zr/177Lu to develop radionuclide theranostic pairs and evaluated the pharmacokinetics and theranostic efficacies of the agents in cell- and patient-derived models. Both C2 and ABDC2 specifically reacted with human CD47 with a high KD value of 23.50 and 84.57 pM, respectively. [68Ga]Ga-NOTA-C2 was developed with high radiochemical purity (99 >%, n = 4) and visualized CD47 expression in the tumors. In comparison to the rapid renal clearance and short half-life of [68Ga]Ga-NOTA-C2, both [68Ga]Ga-NOTA-ABDC2 and [89Zr]Zr-DFO-ABDC2 showed prolonged circulation and increased tumor uptake, with the highest uptake of [89Zr]Zr-DFO-ABDC2 occurring at 72 h post-injection. Moreover, [177Lu]Lu-DOTA-ABDC2 radioimmunotherapy suppressed the tumor growth but was associated with toxicity, warranting further optimization of the treatment schedules. Taken together, we reported a series of nanobody-derived CD47-targeted agents, of which [68Ga]Ga-NOTA-C2 and [89Zr]Zr-DFO-ABDC2 are readily translatable. Optimization and translation of CD47-targeted theranostic pair may provide new prospects for CD47-targeted management of solid tumors.
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影响因子：
82.9
作者：
Liu X;Pu Y;Cron K;Deng L;Kline J;Frazier WA;Xu H;Peng H;Fu YX;Xu MM
通讯作者：
Xu MM
DOI：
10.1126/science.aac9935
发表时间：
2016-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Casey SC;Tong L;Li Y;Do R;Walz S;Fitzgerald KN;Gouw AM;Baylot V;Gütgemann I;Eilers M;Felsher DW
通讯作者：
Felsher DW
CD47是人类急性髓样白血病干细胞的不良预后因素和治疗抗体靶标。
影响因子：
64.5
作者：
Majeti R;Chao MP;Alizadeh AA;Pang WW;Jaiswal S;Gibbs KD Jr;van Rooijen N;Weissman IL
通讯作者：
Weissman IL
影响因子：
12.4
作者：
Cheal SM;McDevitt MR;Santich BH;Patel M;Yang G;Fung EK;Veach DR;Bell M;Ahad A;Vargas DB;Punzalan B;Pillarsetty NVK;Xu H;Guo HF;Monette S;Michel AO;Piersigilli A;Scheinberg DA;Ouerfelli O;Cheung NV;Larson SM
通讯作者：
Larson SM
影响因子：
4.1
作者：
Harmand TJ;Islam A;Pishesha N;Ploegh HL
通讯作者：
Ploegh HL