School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, Geneva, Switzerland.
OncoSynergy, Inc., Greenwich, CT, USA.
Sci Rep. 2019 Jan 31;9(1):1030. doi: 10.1038/s41598-018-36966-0.
Monoclonal antibodies targeting cytokines are administered parenterally for the systemic treatment of severe psoriasis. However, systemic exposure to the biologic increases the risk of side-effects including immunosuppression, whereas only a small fraction of the active molecules actually reaches the target organ, the skin. This preclinical study examines the feasibility of delivering a humanized anti-CD29 monoclonal antibody (OS2966) topically to skin using minimally-invasive fractional laser ablation. This approach would enable the targeted use of a biologic for the treatment of recalcitrant psoriatic plaques in patients with less widespread disease while minimizing the risk of systemic exposure. First, the effect of a wide range of laser poration conditions on skin permeation and deposition of OS2966 was tested in vitro to determine optimal microporation parameters. Subsequently, confocal laser scanning microscopy was employed to visualize the distribution of fluorescently-labelled OS2966 in skin. The results demonstrated that delivery of OS2966 into and across skin was feasible. Above fluences of 35.1 J/cm, skin deposition and permeation were statistically superior to passive delivery reaching values up to 3.7 ± 1.2 µg/cm at the most aggressive condition. Selective targeting of the skin was also possible since ≥70% of the OS2966 was delivered locally to the skin. Although nanogramme quantities were able to permeate across skin, these amounts were orders of magnitude lower than levels seen following subcutaneous or intravenous injection and would result in minimal systemic exposure in vivo. The diffusion of fluorescently-labelled OS2966 into the skin surrounding the pores was clearly higher than in intact skin and demonstrated the feasibility of delivering the antibody at least as deep as the dermo-epithelial junction, a critical border region where inflammatory cells cross to promote disease progression. These preliminary results confirm that fractional laser ablation can be used for the cutaneous delivery of OS2966 and now preclinical/clinical studies are required to demonstrate therapeutic efficacy.
针对细胞因子的单克隆抗体通过注射给药，用于严重银屑病的全身性治疗。然而，生物制剂的全身暴露会增加副作用的风险，包括免疫抑制，而只有一小部分活性分子实际上到达目标器官，即皮肤。这项临床前研究探讨了使用微创分数激光消融术将人源化抗 CD29 单克隆抗体（OS2966）局部递送至皮肤的可行性。这种方法将使生物制剂能够靶向用于治疗患有较少广泛疾病的患者的难治性银屑病斑块，同时最大限度地降低全身暴露的风险。首先，在体外测试了广泛的激光穿孔条件对 OS2966 的皮肤渗透和沉积的影响，以确定最佳微穿孔参数。随后，使用共聚焦激光扫描显微镜观察荧光标记的 OS2966 在皮肤中的分布。结果表明，将 OS2966 递送至皮肤内部和穿过皮肤是可行的。在超过 35.1 J/cm 的辐照下，皮肤沉积和渗透的统计学优于被动递送，在最激进的条件下达到 3.7±1.2μg/cm。由于至少 70%的 OS2966 被局部递送至皮肤，因此还可以实现皮肤的选择性靶向。虽然纳米克数量可以穿过皮肤，但这些数量比皮下或静脉注射后看到的数量低几个数量级，并且在体内会导致最小的全身暴露。荧光标记的 OS2966 向毛孔周围皮肤的扩散明显高于完整皮肤，证明了将抗体递送至至少真皮-表皮交界处（炎症细胞穿过以促进疾病进展的关键边界区域）的深度的可行性。这些初步结果证实，分数激光消融术可用于 OS2966 的皮肤递药，现在需要进行临床前/临床研究以证明治疗效果。
