Department of Oncology, University of Oxford, Oxford, United Kingdom.
Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
Front Immunol. 2022 Jul 28;13:814064. doi: 10.3389/fimmu.2022.814064. eCollection 2022.
Approval of B-cell-depleting therapies signifies an important advance in the treatment of multiple sclerosis (MS). However, it is unclear whether the administration route of anti-CD20 monoclonal antibodies (mAbs) alters tissue distribution patterns and subsequent downstream effects. This study aimed to investigate the distribution and efficacy of radiolabeled ofatumumab and ocrelizumab in humanized-CD20 (huCD20) transgenic mice following subcutaneous (SC) and intravenous (IV) administration. For distribution analysis, huCD20 and wildtype mice (n = 5 per group) were imaged by single-photon emission computed tomography (SPECT)/CT 72 h after SC/IV administration of ofatumumab or SC/IV administration of ocrelizumab, radiolabeled with Indium-111 (In-ofatumumab or In-ocrelizumab; 5 µg, 5 MBq). For efficacy analysis, huCD20 mice with focal delayed-type hypersensitivity lesions and associated tertiary lymphoid structures (DTH-TLS) were administered SC/IV ofatumumab or SC/IV ocrelizumab (7.5 mg/kg, n = 10 per group) on Days 63, 70 and 75 post lesion induction. Treatment impact on the number of CD19+ cells in select tissues and the evolution of DTH-TLS lesions in the brain were assessed. Uptake of an In-labelled anti-CD19 antibody in cervical and axillary lymph nodes was also assessed before and 18 days after treatment initiation as a measure of B-cell depletion. SPECT/CT image quantification revealed similar tissue distribution, albeit with large differences in blood signal, of In-ofatumumab and In-ocrelizumab following SC and IV administration; however, an increase in both mAbs was observed in the axillary and inguinal lymph nodes following SC versus IV administration. In the DTH-TLS model of MS, both treatments significantly reduced the In-anti-CD19 signal and number of CD19+ cells in select tissues, where no differences between the route of administration or mAb were observed. Both treatments significantly decreased the extent of glial activation, as well as the number of B- and T-cells in the lesion following SC and IV administration, although this was mostly achieved to a greater extent with ofatumumab versus ocrelizumab. These findings suggest that there may be more direct access to the lymph nodes through the lymphatic system with SC versus IV administration. Furthermore, preliminary findings suggest that ofatumumab may be more effective than ocrelizumab at controlling MS-like pathology in the brain.
B 细胞耗竭疗法的批准标志着多发性硬化症（MS）治疗的重要进展。然而，尚不清楚抗 CD20 单克隆抗体（mAb）的给药途径是否会改变组织分布模式和随后的下游效应。本研究旨在研究放射性标记的奥法妥木单抗和奥瑞珠单抗在皮下（SC）和静脉内（IV）给药后在人源化-CD20（huCD20）转基因小鼠中的分布和疗效。为了进行分布分析，在 SC/IV 给予奥法妥木单抗或 SC/IV 给予奥瑞珠单抗后 72 小时，huCD20 和野生型小鼠（每组 5 只）通过单光子发射计算机断层扫描（SPECT）/CT 成像，用铟-111（In-奥法妥木单抗或 In-奥瑞珠单抗；5μg，5MBq）标记。为了进行疗效分析，在诱导病变后第 63、70 和 75 天，用 SC/IV 奥法妥木单抗或 SC/IV 奥瑞珠单抗（7.5mg/kg，每组 10 只）治疗具有局灶性迟发型超敏反应病变和相关三级淋巴结构（DTH-TLS）的 huCD20 小鼠。评估了在选定组织中 CD19+细胞数量的变化以及大脑中 DTH-TLS 病变的演变。还在治疗开始前和 18 天后评估了颈和腋窝淋巴结中 In 标记的抗 CD19 抗体的摄取，作为 B 细胞耗竭的衡量标准。SPECT/CT 图像定量显示，SC 和 IV 给药后，In-奥法妥木单抗和 In-奥瑞珠单抗在组织中的分布相似，尽管血液信号差异很大；然而，与 IV 给药相比，SC 给药后观察到两种 mAb 在腋窝和腹股沟淋巴结中的增加。在 MS 的 DTH-TLS 模型中，两种治疗方法均显著降低了 In-抗 CD19 信号和选定组织中 CD19+细胞的数量，在给药途径或 mAb 之间未观察到差异。两种治疗方法均显著降低了胶质细胞激活的程度以及病变中 B 和 T 细胞的数量，尽管与奥瑞珠单抗相比，奥法妥木单抗在这方面的效果更为显著。这些发现表明，与 IV 给药相比，SC 给药可能通过淋巴系统更直接地进入淋巴结。此外，初步研究结果表明，与奥瑞珠单抗相比，奥法妥木单抗在控制大脑中的 MS 样病理学方面可能更有效。
