Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation
Rational Design of Antirheumatic Prodrugs Specific for Sites of Inflammation
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DOI：
10.1002/art.39232
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发表时间：
2015-10-01
影响因子：
13.3
通讯作者：
Pitzalis, Costantino
中科院分区：
文献类型：
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作者：
Onuoha, Shimobi C.;Ferrari, Mathieu;Pitzalis, Costantino
Objective.生物药物，如抗肿瘤坏死因子（抗TNF）抗体阿达木单抗，代表了类风湿关节炎治疗的突破。然而，人们仍然担心它们在相当大比例的患者中缺乏疗效，以及它们潜在的全身副作用，如感染。特异性靶向炎症部位的改进的生物前药有可能缓解目前围绕生物抗细胞因子疗法的担忧。本研究的目的是设计、构建和体外和离体评估可活化双特异性抗体的靶向和抗炎能力。方法。设计并构建了可活化双可变结构域（aDVD）抗体以靶向在炎症部位上调的细胞间粘附分子1（ICAM-1）和抗TNF抗体（阿达木单抗和英夫利昔单抗）。这些双特异性分子包括靶向ICAM-1的外部臂和包含抗TNF抗体的治疗结构域的内部臂。两个臂均连接至基质金属蛋白酶（MMP）可裂解的接头。测试构建体结合和中和体外和离体靶标的能力。与亲本抗体相比，完整的aDVD构建体在前药制剂中表现出显著降低的结合和抗TNF活性。人滑液和生理浓度的MMP酶能够切割抗体的外部结构域，显示出完全活性的分子。活化的抗体保留了与母体分子相同的结合和抗TNF抑制能力。描述了对炎症部位（滑膜）具有增强的特异性和对脱靶TNF具有降低的特异性的生物前药的设计。该构建体具有形成平台技术的潜力，该平台技术能够增强用于治疗RA和其他炎性疾病的药物的治疗指数。
Objective. Biologic drugs, such as the anti-tumor necrosis factor (anti-TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies.Methods. Activatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM-1), which is up-regulated at sites of inflammation, and anti-TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM-1 and an internal arm that comprises the therapeutic domain of an anti-TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)-cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets.Results. Intact aDVD constructs demonstrated significantly reduced binding and anti-TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti- TNF inhibitory capacities as the parent molecules.Conclusion. The design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off- target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases.