Toward further simplification of elotuzumab therapy by subcutaneous administration
Toward further simplification of elotuzumab therapy by subcutaneous administration
复制标题
通过皮下给药进一步简化 elotuzumab 治疗
DOI：
10.1007/s12185-020-02942-6
复制
发表时间：
2020
期刊：
影响因子：
2.1
通讯作者：
Kuroda J
中科院分区：
文献类型：
--
作者：
Shimura Y;Tsukamoto T;Yamaguchi J;Kuwahara-Ota S;Isa R;Nishiyama D;Kobayashi T;Horiike S;Suzuki A;Kuroda J
信号淋巴细胞激活分子 F7 (SLAMF7) 在多发性骨髓瘤 (MM) 细胞表面强烈表达，因此构成 MM 疾病特异性治疗靶点。 Elotuzumab (ELO) 是一种针对 SLAMF7 的人源化 IgG1 单克隆抗体 (MoAb)，是 MM 的主要治疗药物之一，特别是在地塞米松存在的情况下与来那度胺或泊马度胺联合使用。一些临床试验，例如 Kubo 等人的临床试验。最近一期《国际血液学杂志》报道[1]，很好地验证了 ELO 5 mL/min 高速输注的有效性和可行性，比 ELOQUENT-2 研究中最初采用的 2 mL/min 输注速度快了 2.5 倍。正如作者所讨论的[1]，这种“更快”的静脉注射（IV）策略可以使大部分输液在1小时内完成，减轻患者的身体负担，而不增加不良事件，并有可能节省医疗资源。为了进一步开发安全、更方便的途径，我们试图利用小鼠实验模型探索皮下（SC）给予 ELO 的可能性。在本研究中，我们新建立了一种用于测量血清中 ELO 的 ELISA 方法。补充信息中描述了该测定系统的建立和质量验证。使用这种 ELISA 测定，我们通过药代动力学分析检查了 ELO 在小鼠中 SC 递送的效用。 ELO 由 Bristol-Myers Squibb（新泽西州普林斯顿派克）提供，并以 1 mg/mL 的浓度溶解在蒸馏水 (DW) 中。该研究使用六周大的雄性 Crl: CD1 小鼠（日本查尔斯河实验室）。通过实验前一天的体重调整，将30只小鼠分为SC治疗组和腹膜内（IP）治疗组。每组由 15 只小鼠组成，两组的平均体重相似：SC 组和 IP 组分别为 33.4 克和 33.2 克。 ELO以10 mg/kg（与临床使用剂量相同）单剂量背部皮下注射（SC组）或直接注射到腹膜腔（IP组）。使用开发的 ELISA 在 ELO 注射后 0.5、1、3、10 和 24 小时测量 ELO 的血清浓度。在每个时间点，从三只小鼠采集血液样本。该协议是根据国家动物实验指南进行的，并得到机构动物护理和使用委员会的批准（批准号 T180116）。结果，ELO的血清浓度持续增加至54.8±8.9 μg/mL，直到24小时才达到最大浓度（C max）。在IP组中，血清ELO在给药后3小时达到最大值，此后逐渐下降（图1）。无论采用何种途径，ELO 给药后，小鼠均未表现出任何异常行为或症状。我们的结果首次表明，通过皮下注射 10 mg/kg ELO 成功进行了 ELO 血液移植，其生物活性浓度使 SLAMF7 在骨髓瘤患者 > 90% 的 CD38 阳性骨髓细胞上饱和 [2]。不幸的是，在本研究中，ELO 的皮下吸收意外缓慢，使我们无法获得其血清 C max 或达到 C max 的时间。然而，它会
Signaling lymphocyte activation molecule F7 (SLAMF7) is strongly expressed on the surface of multiple myeloma (MM) cells, and therefore, constitutes a disease-specific therapeutic target for MM. Elotuzumab (ELO), a humanized IgG1 monoclonal antibody (MoAb) against SLAMF7, is one of the central treatment agents for MM, especially in combination with lenalidomide or pomalidomide in the presence of dexamethasone. Several clinical trials, such as that by Kubo et al. reported in the recent issue of International Journal of Hematology [1], have nicely validated the efficacy and feasibility of the high-speed infusion of ELO at 5 mL/min, which is 2.5-fold faster than the originally adopted infusion rate at 2 mL/min in ELOQUENT-2 study. As discussed by authors [1], this “faster” intravenous (IV) strategy allows most infusion to be completed within 1 h, reduces patients’ physical burden without increase of adverse events, and potentially saves medical resources. To further develop a safe and more convenient route, we herein sought to explore the possibility for subcutaneous (SC) administration of ELO using mice experimental model. For this study, we newly established an ELISA for measurement of ELO in serum. The establishment and the quality validation of this assay system were described in Supplementary information. Using this ELISA assay, we examined the utility of SC delivery of ELO in mice by pharmacokinetic analysis. ELO was provided by Bristol-Myers Squibb (Princeton Pike, NJ), and was dissolved at 1 mg/mL in distilled water (DW). Six-week-old male Crl: CD1 mice (Charles River Laboratories Japan) were used in the study. With adjustment for body weight on the day before experiments, 30 mice were divided into SC and intraperitoneal (IP) treatment groups. Each group consisted of 15 mice and the mean body weight was similar in the two groups: 33.4 g and 33.2 g in the SC and IP groups, respectively. ELO was injected at 10 mg/kg (same as the dose clinically used) as a single dose subcutaneously on the back (SC group) or directly into the peritoneal cavity (IP group). Serum concentrations of ELO were measured at 0.5, 1, 3, 10 and 24 h after ELO injection using the developed ELISA. At each time point, blood samples were collected from three mice. This protocol was performed in accordance with the national guidelines for animal experiments and was approved by the institutional animal care and use committee (Approved No. T180116). As the results, the serum concentration of ELO continued to increase up to 54.8±8.9 μg/mL and did not reach maximum concentration (C max) until 24 h. In the IP group, serum ELO reached a maximum at 3 h after administration, and gradually declined thereafter (Fig. 1). No mouse showed any abnormal behavior or symptoms after ELO administration, regardless of the route. Our results for the first time showed the successful blood transfer of ELO by SC administration of 10 mg/kg ELO which achieves the biologically active concentration that saturates SLAMF7 on> 90% of CD38-positive bone marrow cells in patients with myeloma [2]. Unfortunately, unexpected slow subcutaneous absorption of ELO precluded us from accessing its serum C max or time to C max in this study. However, it would