CD47 的过度表达在各种人类恶性肿瘤中经常被观察到，抑制粒细胞介导的肿瘤细胞清除，影响癌症患者的预后。通过映射生物标记物表达，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 CD47 免疫羊驼，我们准备了一个 CD47-靶向的纳米体 C2，并开发了[68Ga]Ga-NOTA-C2，随后对 CD47-表达的肿瘤模型进行了诊断价值的探索，包括胃癌患者源性异种移植模型。通过将 C2 融合到白蛋白结合域（ABD）中，我们合成了 ABDC2，其体内半衰期增加，靶向性能得到改善。我们进一步将 ABDC2 标记为 68Ga/89Zr/177Lu，开发放射性核素治疗-诊断配对，并在细胞和患者来源的模型中评估了药代动力学和治疗有效性。C2 和 ABDC2 都特异性地与人类 CD47 反应，其 K D 值分别为 23.50 和 84.57 pM。[68Ga]Ga-NOTA-C2 的放射化学纯度高（99 ％以上，n = 4），并且在肿瘤中显示出 CD47 的表达。与[68Ga]Ga-NOTA-C2 的快速肾清除和短半衰期相比，[68Ga]Ga-NOTA-ABDC2 和 [89Zr]Zr-DFO-ABDC2 都显示出延长的循环和增加的肿瘤摄取， [89Zr]Zr-DFO-ABDC2 在注射后 72 小时呈现最高摄取率。此外，[177Lu]Lu-DOTA-ABDC2 放射免疫疗法抑制了肿瘤生长，但与毒性有关，需要进一步优化治疗方案。总之，我们报告了一系列的纳米体衍生的 CD47-靶向剂，其中[68Ga]Ga-NOTA-C2 和 [89Zr]Zr-DFO-ABDC2 易于转化。 CD47 靶向治疗诊断配对的优化和转化可以为实体瘤的 CD47 靶向管理提供新的前景。

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 K D 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.