Medgenics Medical Israel, Ltd, Misgav, Israel.
Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Israel.
J Gene Med. 2017 Aug;19(8). doi: 10.1002/jgm.2965.
Rheumatoid arthritis (RA) is a symmetric inflammatory polyarthritis associated with high concentrations of pro-inflammatory, cytokines including tumor necrosis factor (TNF)-α. Adalimumab is a monoclonal antibody (mAb) that binds TNF-α, and is widely used to treat RA. Despite its proven clinical efficacy, adalimumab and other therapeutic mAbs have disadvantages, including the requirement for repeated bolus injections and the appearance of treatment limiting anti-drug antibodies. To address these issues, we have developed an innovative ex vivo gene therapy approach, termed transduced autologous restorative gene therapy (TARGT), to produce and secrete adalimumab for the treatment of RA.
Helper-dependent (HD) adenovirus vector containing adalimumab light and heavy chain coding sequences was used to transduce microdermal tissues and cells of human and mouse origin ex vivo, rendering sustained secretion of active adalimumab. The genetically engineered tissues were subsequently implanted in a mouse model of RA.
Transduced human microdermal tissues implanted in SCID mice demonstrated 49 days of secretion of active adalimumab in the blood, at levels of tens of microgram per milliliter. In addition, transduced autologous dermal cells were implanted in the RA mouse model and demonstrated statistically significant amelioration in RA symptoms compared to naïve cell implantation and were similar to recombinant adalimumab bolus injections.
The results of the present study report microdermal tissues engineered to secrete active adalimumab as a proof of concept for sustained secretion of antibody from the novel ex vivo gene therapy TARGT platform. This technology may now be applied to a range of antibodies for the therapy of other diseases.
类风湿关节炎（RA）是一种对称性炎症性多关节炎，与高浓度促炎细胞因子有关，包括肿瘤坏死因子（TNF）-α。阿达木单抗是一种单克隆抗体（mAb），可与 TNF-α结合，广泛用于治疗 RA。尽管阿达木单抗和其他治疗性 mAb 已被证实具有临床疗效，但仍存在一些缺点，包括需要反复进行大剂量注射和出现治疗性抗药物抗体。为了解决这些问题，我们开发了一种创新的体外基因治疗方法，称为转导自体修复基因治疗（TARGT），以产生和分泌阿达木单抗治疗 RA。
使用含有阿达木单抗轻链和重链编码序列的辅助依赖性（HD）腺病毒载体对人源和鼠源微真皮组织和细胞进行体外转导，以持续分泌活性阿达木单抗。随后将基因工程组织植入 RA 小鼠模型中。
植入 SCID 小鼠的转导人微真皮组织在血液中持续分泌活性阿达木单抗 49 天，水平为数十微克/毫升。此外，将转导的自体真皮细胞植入 RA 小鼠模型中，与未转导细胞植入相比，RA 症状得到了统计学上的显著改善，与重组阿达木单抗大剂量注射相似。
本研究的结果报告了经基因工程改造以分泌活性阿达木单抗的微真皮组织，为新型体外基因治疗 TARGT 平台从抗体的持续分泌提供了概念验证。该技术现在可应用于一系列抗体，用于治疗其他疾病。
