Philochem AG, c/o ETH Zurich, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Strasse 10 HCI E520, CH-8093 Zurich, Switzerland.
Arthritis Res Ther. 2009;11(5):R142. doi: 10.1186/ar2814. Epub 2009 Sep 25.
In this article, we present a comparative immunohistochemical evaluation of four clinical-stage antibodies (L19, F16, G11 and F8) directed against splice isoforms of fibronectin and of tenascin-C for their ability to stain synovial tissue alterations in rheumatoid arthritis patients. Furthermore we have evaluated the therapeutic potential of the most promising antibody, F8, fused to the anti-inflammatory cytokine interleukin (IL) 10.
F8-IL10 was produced and purified to homogeneity in CHO cells and shown to comprise biological active antibody and cytokine moieties by binding assays on recombinant antigen and by MC/9 cell proliferation assays. We have also characterized the ability of F8-IL10 to inhibit arthritis progression in the collagen-induced arthritis mouse model.
The human antibody F8, specific to the extra-domain A of fibronectin, exhibited the strongest and most homogenous staining pattern in synovial biopsies and was thus selected for the development of a fully human fusion protein with IL10 (F8-IL10, also named DEKAVIL). Following radioiodination, F8-IL10 was able to selectively target arthritic lesions and tumor neo-vascular structures in mice, as evidenced by autoradiographic analysis and quantitative biodistribution studies. The subcutaneous administration route led to equivalent targeting results when compared with intravenous administration and was thus selected for the clinical development of the product. F8-IL10 potently inhibited progression of established arthritis in the collagen-induced mouse model when tested alone and in combination with methotrexate. In preparation for clinical trials in patients with rheumatoid arthritis, F8-IL10 was studied in rodents and in cynomolgus monkeys, revealing an excellent safety profile at doses tenfold higher than the planned starting dose for clinical phase I trials.
Following the encouraging preclinical results presented in this paper, clinical trials with F8-IL10 will now elucidate the therapeutic potential of this product and whether the targeted delivery of IL10 potentiates the anti-arthritic action of the cytokine in rheumatoid arthritis patients.
本文介绍了针对纤维连接蛋白剪接异构体和 tenascin-C 的四种临床阶段抗体（L19、F16、G11 和 F8）的免疫组化比较评估，以评估它们在类风湿关节炎患者滑膜组织改变中的染色能力。此外，我们还评估了最有前途的抗体 F8 与抗炎细胞因子白细胞介素（IL）10 融合的治疗潜力。
F8-IL10 在 CHO 细胞中产生和纯化至均一性，并通过对重组抗原的结合测定和 MC/9 细胞增殖测定显示包含生物活性抗体和细胞因子部分。我们还表征了 F8-IL10 抑制胶原诱导关节炎小鼠模型中关节炎进展的能力。
针对纤维连接蛋白外显子 A 的人源抗体 F8 在滑膜活检中表现出最强和最均匀的染色模式，因此被选为与白细胞介素 10（F8-IL10，也称为 DEKAVIL）融合的完全人源融合蛋白的开发。放射性碘标记后，F8-IL10 能够通过放射性自显影分析和定量生物分布研究选择性地靶向关节炎病变和肿瘤新生血管结构。与静脉内给药相比，皮下给药途径导致等效的靶向结果，因此被选为该产品的临床开发。当单独测试和与甲氨蝶呤联合测试时，F8-IL10 可有效抑制胶原诱导的小鼠模型中已建立的关节炎的进展。在准备进行类风湿关节炎患者的临床试验之前，在啮齿动物和食蟹猴中研究了 F8-IL10，发现其在比计划用于 I 期临床试验的起始剂量高十倍的剂量下具有极好的安全性。
根据本文中提供的令人鼓舞的临床前结果，现在将进行 F8-IL10 的临床试验，以阐明该产品的治疗潜力，以及白细胞介素 10 的靶向递送是否增强了类风湿关节炎患者细胞因子的抗关节炎作用。
