Daratumumab-225Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
Daratumumab-225Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors
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DOI：
10.1080/2162402x.2019.1607673
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发表时间：
2019-05-02
期刊：
影响因子：
7.2
通讯作者：
Dadachova, Ekaterina
中科院分区：
文献类型：
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作者：
Dawicki, Wojciech;Allen, Kevin J. H.;Dadachova, Ekaterina
Daratumumab 是一种抗 CD38 定向单克隆抗体，被批准用于治疗多发性骨髓瘤 (MM)，主要通过 Fc 介导的效应机制发挥作用，例如补体依赖性细胞毒性 (CDC)、抗体依赖性细胞毒性 (ADCC)、抗体依赖性细胞吞噬作用和 T 细胞激活。然而，并非所有患者都对达雷妥尤单抗治疗有反应，多发性骨髓瘤的治疗仍然具有挑战性。使用发射α粒子的放射性核素进行放射免疫治疗是一种有前途的方法，可以显着增强治疗性抗体在癌症治疗中的效力。在此，我们报告使用 α 发射体 (225) 锕放射性标记的 daratumumab 治疗 MM 的机制和可行性研究结果。 CD38 阳性淋巴瘤 Daudi 细胞系和 MM 细胞系 KMS-28BM 和 KMS-28PE 在体外用 Ac-225-daratumumab 处理。通过 C1q 结合和 ADCC 测定评估 Ac-225-daratumumab Fc 功能特性。使用 microSPECT/CT 测量了 In-111-daratumumab 在 Daudi 肿瘤严重联合免疫缺陷 (SCID) 小鼠中的药代动力学和肿瘤摄取。治疗后 50 天评估 Ac-225-daratumumab 对小鼠 Daudi 和 KSM28BM 肿瘤的治疗效果以及治疗副作用。还评估了 Ac-225 标记的抗鼠 CD38 mAb 在免疫功能正常的小鼠中的安全性。 Ac-225-daratumumab 在体外有效且特异性地杀死 CD38 阳性肿瘤细胞，而其补体结合和 ADCC 功能保持不变。 MicroSPECT/CT 成像显示放射性标记的 daratumumab 从循环和组织中快速清除，但在肿瘤中的保留时间延长长达 10 天。 Ac-225-daratumumab 的治疗和安全性实验显示，与裸抗体相比，抗肿瘤效力显着增加，且没有任何明显副作用。我们的结果强调了将 α 发射体靶向肿瘤作为治疗方法的潜力，并表明 Ac-225-daratumumab 可能是治疗血液恶性肿瘤的一种有前途的治疗策略。
Daratumumab is an anti-CD38 directed monoclonal antibody approved for the treatment of multiple myeloma (MM) and functions primarily via Fc-mediated effector mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and T-cell activation. However, not all patients respond to daratumumab therapy and management of MM remains challenging. Radioimmunotherapy with alpha particle-emitting radionuclides represents a promising approach to significantly enhance the potency of therapeutic antibodies in cancer treatment. Here we report the results of mechanistic and feasibility studies using daratumumab radiolabeled with an alpha-emitter (225)Actinium for therapy of MM. CD38-positivelymphoma Daudi cell line and MM cell lines KMS-28BM and KMS-28PE were treated in vitro with Ac-225-daratumumab. Ac-225-daratumumab Fc-functional properties were assessed with C1q binding and ADCC assays. The pharmacokinetics and tumor uptake of In-111-daratumumab in Daudi tumor-bearing severe combined immunodeficiency (SCID) mice were measured with microSPECT/CT. The therapeutic effects of Ac-225-daratumumab on Daudi and KSM28BM tumors in mice and treatment side effects were evaluated for 50 days posttreatment. The safety of Ac-225-labeled antimurine CD38 mAb in immunocompetent mice was also evaluated. Ac-225-daratumumab efficiently and specifically killed CD38-positive tumor cells in vitro, while its complement binding and ADCC functions remained unaltered. MicroSPECT/CT imaging demonstrated fast clearance of the radiolabeled daratumumab from the circulation and tissues, but prolonged retention in the tumor up to 10 days. Therapy and safety experiments with Ac-225-daratumumab showed a significant increase in the antitumor potency in comparison to naked antibody without any significant side effects. Our results highlight the potential of targeting alpha-emitters to tumors as a therapeutic approach and suggest that Ac-225-daratumumab may be a promising therapeutic strategy for the treatment of hematologic malignancies.