Purpose

CD38 is a glycoprotein highly specific to multiple myeloma (MM). Therapeutics using antibodies targeting CD38 have shown promising efficacy. However, the efficient stratification of patients who may benefit from daratumumab (Dara) therapy and timely monitoring of therapeutic responses remain significant clinical challenges. To address these issues, we developed a novel nanobody-based PET tracer, [⁶⁸Ga]Ga-TOHP-CD3813, which exhibits rapid clearance from the blood and rapid accumulation in targeted tumor lesions, facilitating the detection of CD38 expression in murine models of MM and lymphoma. Furthermore, we conducted the world’s first-in-human trials using CD38-targeted nanobodies to validate and assess the clinical imaging effectiveness of [⁶⁸Ga]Ga-TOHP-CD3813 in guiding cancer immunotherapy.

Materials and methods

We prepared a new PET imaging probe based on a CD38-targeted nanobody CD3813, [⁶⁸Ga]Ga-TOHP-CD3813, via the site-specific radiolabeling for noninvasive PET imaging of CD38 expression. [⁶⁸Ga]Ga-TOHP-CD3813 was assessed for its affinity and specificity to CD38 and its ability to image CD38 expression in MM and lymphoma xenograft models. Biodistribution and the relationship between tumor uptake and CD38 expression were evaluated. Subsequently, we conducted a translational PET imaging of 2 MM patients using [⁶⁸Ga]Ga-TOHP-CD3813, while compared with [¹⁸F]FDG PET/CT head-to-head. Dosimetry was also calculated based on the animal data.

Results

TOHP-CD3813 retained a high affinity for CD38 with a KD of 0.0826 nmol/L. [⁶⁸Ga]Ga-TOHP-CD3813 was successfully synthesized at room temperature within 10 min, exhibiting optimal radiochemical properties. Preclinical assessments revealed rapid blood clearance, high CD38 affinity, and significant uptake in CD38-positive xenograft mouse models (6.50 ± 2.69%ID/g). [⁶⁸Ga]Ga-TOHP-CD3813 showed pronounced accumulation in the kidneys and bladder, with moderate liver uptake, indicating its potential as a viable clinical PET radiotracer for diagnosing MM. Additionally, in first-in-human trials, [⁶⁸Ga]Ga-TOHP-CD3813 PET/CT provides a substantial improvement over [¹⁸F]FDG PET/CT for the visualization of MM.

Conclusions

[⁶⁸Ga]Ga-TOHP-CD3813, with its high affinity, specificity, and robust imaging capabilities, rapidly and specifically accumulates in tumors with high CD38 expression, offering a significant advantage over [¹⁸F]FDG PET/CT for visualizing MM and enabling same-day PET imaging. Initial human trial results are promising, suggesting its potential as a companion diagnostic tool for optimizing CD38-targeted treatments in tumors. Ongoing larger trials aim to further confirm these findings.

中文翻译：

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用于多发性骨髓瘤诊断和治疗监测的 CD38 特异性免疫 PET 成像：临床前和首次人体研究

 目的

CD38 是一种对多发性骨髓瘤 （MM） 高度特异性的糖蛋白。使用靶向 CD38 的抗体的治疗已显示出有希望的疗效。然而，对可能受益于 daratumumab （Dara） 治疗的患者进行有效分层和及时监测治疗反应仍然是重大的临床挑战。为了解决这些问题，我们开发了一种基于纳米抗体的新型 PET 示踪剂 [⁶⁸Ga]Ga-TOHP-CD3813，它表现出从血液中快速清除并在靶向肿瘤病灶中快速积累，有助于检测 MM 和淋巴瘤小鼠模型中的 CD38 表达。此外，我们进行了世界上第一个使用 CD38 靶向纳米抗体的人体试验，以验证和评估 [⁶⁸Ga]Ga-TOHP-CD3813 在指导癌症免疫治疗中的临床成像有效性。

 材料和方法

我们通过位点特异性放射性标记制备了基于 CD38 靶向纳米抗体 CD3813 [⁶⁸Ga]Ga-TOHP-CD3813 的新型 PET 成像探针，用于 CD38 表达的无创 PET 成像。[⁶⁸加]评估了 Ga-TOHP-CD3813 对 CD38 的亲和力和特异性，以及它在 MM 和淋巴瘤异种移植模型中对 CD38 表达进行成像的能力。评估生物分布以及肿瘤摄取与 CD38 表达之间的关系。随后，我们使用 [⁶⁸Ga]Ga-TOHP-CD3813 对 2 MM 患者进行了翻译 PET 成像，同时与 [¹⁸F]FDG PET/CT 头对头进行比较。剂量测定也根据动物数据计算。

 结果

TOHP-CD3813 对 CD38 保持高亲和力，KD 为 0.0826 nmol/L。[⁶⁸Ga]Ga-TOHP-CD3813 在室温下 10 分钟内成功合成，表现出最佳的放射化学性质。临床前评估显示，CD38 阳性异种移植小鼠模型 （6.50 ± 2.69%ID/g） 具有快速血液清除率、高 CD38 亲和力和显著摄取。[⁶⁸加]Ga-TOHP-CD3813 在肾脏和膀胱中表现出明显的蓄积，肝脏摄取适度，表明其作为诊断 MM 的可行临床 PET 放射性示踪剂的潜力。此外，在首次人体试验中，[⁶⁸Ga]Ga-TOHP-CD3813 PET/CT 在 MM 可视化方面比 [¹⁸F]FDG PET/CT 有显着改善。

 结论

[⁶⁸加]Ga-TOHP-CD3813 具有高亲和力、特异性和强大的成像能力，可在 CD38 高表达的肿瘤中快速、特异性地积累，与 [¹⁸F]FDG PET/CT 相比，在可视化 MM 和实现当天 PET 成像方面具有显著优势。初步人体试验结果很有希望，表明它有可能作为优化肿瘤 CD38 靶向治疗的伴随诊断工具。正在进行的更大规模的试验旨在进一步证实这些发现。