具有双功能抗炎作用的抗体-药物偶联物在类风湿关节炎发病中的治疗潜力

IF 4.9 2区 医学 Q1 Medicine Arthritis Research & Therapy Pub Date : 2024-12-19 DOI:10.1186/s13075-024-03452-0
Tanu Dixit, Anuradha Vaidya, Selvan Ravindran
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引用次数: 0

摘要

在一个发展精准药物的时代,抗体-药物偶联物(adc)已经成为一种渐进的治疗策略。adc通常由单克隆抗体(mAb)组成,通过连接物与细胞毒性有效载荷结合,结合单克隆抗体的明确靶标特异性和有效载荷的强大杀伤作用,实现精确有效地消除靶细胞。除了在肿瘤学中已确立的作用外,adc目前在解决类风湿关节炎(RA)等自身免疫性疾病治疗中未满足的需求方面显示出令人鼓舞的潜力。常见的长期自身免疫性疾病类风湿性关节炎每年花费数十亿美元,但仍然缺乏副作用最小的精确靶向治疗方法。本文综述了RA的发病机制、已有的治疗方法及其局限性、adc在RA治疗中的应用、adc的作用机制以及adc在临床前和临床试验中的研究进展。在文献的基础上,我们还提出了一种ADC合成策略,这可能会提高针对多因子疾病(如RA)的效率。我们建议利用风湿性关节炎的一线治疗药物DMARDs(疾病改善抗风湿药物)作为ADC合成的有效载荷。dmard是唯一一类限制疾病进展的药物,但由于脱靶毒性,其疗效有限。因此,利用它们作为有效载荷将有助于将它们直接递送到目标部位,减少它们的脱靶毒性,从而提高它们靶向疾病的效率。此外,由于单克隆抗体不足以达到缓解,它们与dmard联合使用。因此,合成adc可以减少给患者的多次和更高剂量,这反过来可以提高患者的依从性。
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Therapeutic potential of antibody-drug conjugates possessing bifunctional anti-inflammatory action in the pathogenies of rheumatoid arthritis
In an age where there is a remarkable upsurge in developing precision medicines, antibody-drug conjugates (ADCs) have emerged as a progressive therapeutic strategy. ADCs typically consist of monoclonal antibodies (mAb) conjugated to the cytotoxic payloads by utilizing a linker, combining the benefits of definitive target specificity of mAbs and potent killing impact of payload to achieve precise and efficient elimination of target cells. In addition to their well-established role in oncology, ADCs are currently demonstrating encouraging potential in addressing the unmet requirements in the treatment of autoimmune conditions such as rheumatoid arthritis (RA). Prevalent long-term autoimmune disease RA costs billions of dollars annually but still, there is a lack of precision-targeted therapeutics with minimal side effects. This review provides an overview of the RA pathogenesis, pre-existing therapies, and their limitations, the introduction of ADCs in RA treatment, the mechanism of ADCs, and a summary of ADCs in preclinical and clinical trials. Based on the literature we also propose a strategy in ADC synthesis, which may increase the efficiency in targeting multifactorial diseases like RA. We propose to utilize DMARDs (Disease-modifying anti-rheumatic drugs), the first-line treatment for RA, as a payload for ADC synthesis. DMARDs are the only class of medication that limits the disease progression, but their efficacy is limited due to off-target toxicities. Hence, utilizing them as payload will help to deliver them directly at the targeted site, reducing their off-target toxicity, which in turn will increase their efficiency in targeting disease. Also, as mAbs are not sufficient to achieve remission, they are given in combinations with DMARDs. Hence, synthesizing ADCs may reduce the multiple and higher dosages given to patients, which in turn may enhance patient compliance.
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来源期刊
CiteScore
8.60
自引率
2.00%
发文量
261
审稿时长
14 weeks
期刊介绍: Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.
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