关节内注射 B 细胞耗竭抗体可增强胶原性关节炎小鼠关节引流淋巴结的局部暴露,Molecular Pharmaceutics

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关节内注射 B 细胞耗竭抗体可增强胶原性关节炎小鼠关节引流淋巴结的局部暴露
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2023-03-21 , DOI: 10.1021/acs.molpharmaceut.2c01041
Alina D Lam ₁ , Ian K Styles ₁ , Danielle Senyschyn ₁ , Enyuan Cao ₁ , Abel Anshabo ₁ , Mohammad Abdallah ₁ , Reyaj Mikrani ₁ , Cameron J Nowell ₂ , Christopher J H Porter ₁ , Orlagh M Feeney ₁ , Natalie L Trevaskis ₁

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关节引流淋巴管内免疫细胞数量、类型和功能的变化是炎症性关节炎进展的主要原因。特别是，关节引流淋巴结 (jdLN) 中的致病性 B 细胞显着扩增。这些 B 细胞似乎会堵塞淋巴结中的淋巴窦，抑制淋巴液流动，从而减少炎症液体和细胞从关节中的清除。总之，有可能更有效地治疗炎症性关节炎，并减少脱靶副作用，将 B 细胞耗竭疗法局部递送至 jdLN。我们最近报道了生物疾病缓解抗风湿药物 (DMARD) 的关节引流淋巴暴露，包括 B 细胞耗竭抗体利妥昔单抗，与皮下 (SC) 或静脉内 (IV) 给药相比，健康大鼠在关节内 (IA) 给药后增加。这表明，与标准 SC 或 IV 给药相比，IA 给药 B 细胞耗竭抗体可能会增加向 jdLN 中靶细胞的递送并提高 B 细胞耗竭的有效性。然而，在炎症性关节炎的情况下，IA 注射后是否也能增强 DMARD 向 jdLN 的局部递送，其中关节有炎症且 jdLN B 细胞扩增尚不清楚。因此，我们评估了 IA、SC、或与患有胶原性关节炎 (CIA) 的小鼠相比，在健康小鼠中静脉注射荧光标记的小鼠抗 CD20 B 细胞耗竭抗体 (Cy5-αCD20)。Cy5-αCD20 的吸收和血浆药代动力学在患有 CIA 的小鼠中似乎没有改变，而在患有 CIA 的小鼠中，Cy5-αCD20 到 jdLNs 的分布通常增加，无论给药途径如何。然而，IA 管理导致更多和更具体的 jdLN 暴露。与健康小鼠相比，CIA 的 jdLNs 中 Cy5-αCD20 增加，与 SC 和 IV 给药相比，与 IA 后 4 小时相比，jdLN 重量减少更多，并且 jdLN B 细胞耗竭的趋势更大。综合起来，

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Intra-articular Injection of a B Cell Depletion Antibody Enhances Local Exposure to the Joint-Draining Lymph Node in Mice with Collagen-Induced Arthritis

Changes to the number, type, and function of immune cells within the joint-draining lymphatics is a major contributor to the progression of inflammatory arthritis. In particular, there is a significant expansion in pathogenic B cells in the joint-draining lymph node (jdLN). These B cells appear to clog the lymphatic sinuses in the lymph node, inhibit lymph flow, and therefore, reduce the clearance of inflammatory fluid and cells from the joint. Taken together, there is potential to treat inflammatory arthritis more effectively, as well as reduce off-target side effects, with localized delivery of B-cell depleting therapies to the jdLNs. We recently reported that joint-draining lymphatic exposure of biologic disease-modifying anti-rheumatic drugs (DMARDs), including the B cell depletion antibody rituximab, is increased in healthy rats following intra-articular (IA) compared to subcutaneous (SC) or intravenous (IV) administration. This suggests that IA administration of B cell depleting antibodies may increase delivery to target cells in the jdLN and increase the effectiveness of B cell depletion compared to standard SC or IV administration. However, whether enhanced local delivery of DMARDs to the jdLN is also achieved after IA injection in the setting of inflammatory arthritis, where there is inflammation in the joint and jdLN B cell expansion is unknown. We, therefore, assessed the lymph node distribution, absorption and plasma pharmacokinetics, and B cell depletion at different sites after IA, SC, or IV administration of a fluorescently labeled mouse anti-CD20 B cell depleting antibody (Cy5-αCD20) in healthy mice compared to mice with collagen-induced arthritis (CIA). The absorption and plasma pharmacokinetics of Cy5-αCD20 appeared unaltered in mice with CIA whereas distribution of Cy5-αCD20 to the jdLNs was generally increased in mice with CIA, regardless of the route of administration. However, IA administration led to greater and more specific exposure to the jdLNs. Consistent with increased Cy5-αCD20 in the jdLNs of CIA compared to healthy mice, there was a greater reduction in jdLN weight and a trend toward greater jdLN B cell depletion at 24 h compared to 4 h after IA compared to SC and IV administration. Taken together, this data supports the potential to improve local efficacy of B cell depletion therapies through a jdLN-directed approach which will enable a reduction in dose and systemic toxicities.

更新日期：2023-03-21

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