Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
Arch Biochem Biophys. 2013 Apr 1;532(1):15-22. doi: 10.1016/j.abb.2012.12.020. Epub 2013 Jan 18.
The efficacy of biological therapeutics against cartilage degradation in osteoarthritis is restricted by the limited transport of macromolecules through the dense, avascular extracellular matrix. The availability of biologics to cell surface and matrix targets is limited by steric hindrance of the matrix, and the microstructure of matrix itself can be dramatically altered by joint injury and the subsequent inflammatory response. We studied the transport into cartilage of a 48 kDa anti-IL-6 antigen binding fragment (Fab) using an in vitro model of joint injury to quantify the transport of Fab fragments into normal and mechanically injured cartilage. The anti-IL-6 Fab was able to diffuse throughout the depth of the tissue, suggesting that Fab fragments can have the desired property of achieving local delivery to targets within cartilage, unlike full-sized antibodies which are too large to penetrate beyond the cartilage surface. Uptake of the anti-IL-6 Fab was significantly increased following mechanical injury, and an additional increase in uptake was observed in response to combined treatment with TNFα and mechanical injury, a model used to mimic the inflammatory response following joint injury. These results suggest that joint trauma leading to cartilage degradation can further alter the transport of such therapeutics and similar-sized macromolecules.
生物疗法在对抗骨关节炎软骨降解方面的疗效受到大分子通过致密、无血管细胞外基质的有限转运的限制。生物制剂到达细胞表面和基质靶点的有效性受到基质空间位阻的限制，而基质本身的微观结构会因关节损伤和随后的炎症反应而发生显著改变。我们使用关节损伤的体外模型研究了 48 kDa 的抗 IL-6 抗原结合片段 (Fab) 在软骨中的转运，以定量评估 Fab 片段进入正常和机械损伤软骨的转运情况。抗 IL-6 Fab 能够扩散到组织的整个深度，这表明 Fab 片段可以具有实现局部递送至软骨内靶标所需的特性，而全尺寸抗体则太大，无法穿透软骨表面以外。机械损伤后，抗 IL-6 Fab 的摄取量显著增加，而在 TNFα 和机械损伤联合治疗时观察到摄取量的进一步增加，这是一种模拟关节损伤后炎症反应的模型。这些结果表明，导致软骨降解的关节创伤可能进一步改变此类治疗药物和类似大小的大分子的转运。
