Lam Alina D, Styles Ian K, Senyschyn Danielle, Cao Enyuan, Anshabo Abel, Abdallah Mohammad, Mikrani Reyaj, Nowell Cameron J, Porter Christopher J H, Feeney Orlagh M, Trevaskis Natalie L
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 399 Royal Parade, Parkville, Victoria 3052, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville Campus, 399 Royal Parade, Parkville, Victoria 3052, Australia.
Mol Pharm. 2023 Apr 3;20(4):2053-2066. doi: 10.1021/acs.molpharmaceut.2c01041. Epub 2023 Mar 21.
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.
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因素。特别是，关节引流淋巴结（jdLN）中致病性B细胞显著扩增。这些B细胞似乎会堵塞淋巴结中的淋巴窦，抑制淋巴流动，从而减少关节中炎性液体和细胞的清除。综上所述，通过向jdLN局部递送B细胞耗竭疗法，有可能更有效地治疗炎症性关节炎，并减少脱靶副作用。我们最近报道，与皮下（SC）或静脉内（IV）给药相比，健康大鼠关节内（IA）注射生物性改善病情抗风湿药（DMARDs）（包括B细胞耗竭抗体利妥昔单抗）后，关节引流淋巴管对其的暴露增加。这表明与标准的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，即关节存在炎症且jdLN B细胞扩增时，IA注射后是否也能增强DMARDs向jdLN的局部递送尚不清楚。因此，我们评估了在健康小鼠和胶原诱导性关节炎（CIA）小鼠中，IA、SC或IV给药荧光标记的小鼠抗CD20 B细胞耗竭抗体（Cy5-αCD20）后，不同部位的淋巴结分布、吸收和血浆药代动力学以及B细胞耗竭情况。在CIA小鼠中，Cy5-αCD20的吸收和血浆药代动力学似乎未改变，而无论给药途径如何，CIA小鼠中Cy5-αCD20向jdLN的分布通常增加。然而，IA给药导致对jdLN的暴露更多且更具特异性。与健康小鼠相比，CIA小鼠的jdLN中Cy5-αCD20增加，与SC和IV给药相比，IA给药后24小时jdLN重量的减少更大，且有jdLN B细胞耗竭程度更大的趋势。综上所述，这些数据支持通过jdLN导向方法提高B细胞耗竭疗法局部疗效的潜力，这将能够降低剂量和全身毒性。
