肿瘤抗体药物偶联物的研发进展和挑战

Research advances and challenges of antibody-drug conjugate for cancer

抗体药物偶联物(antibody-drug conjugate,ADC)是通过连接子将抗体和小分子载荷药物进行连接,利用抗体作为载体将小分子载荷毒素靶向运输至目标细胞的新型药物。随着国内首款ADC药物维迪西妥单抗的上市,ADC药物的临床应用日益广泛。截至2022年2月,临床试验网站www.ClinicalTrial.gov显示有1685项注册临床试验正在开展。目前,全球共批准14款ADC药物上市,其中美国获批12款,日本和中国各1款。随着对ADC药物作用机制的理解加深和新药研发技术的不断突破,促使构成此类药物的抗体、载荷毒素、连接子及偶联技术均有飞速的发展。但是,ADC药物还存在诸多问题和挑战,如发展新型载荷毒素、降低异质性、保证均一性和稳定性等。为了更好地理解ADC药物的性质,本文就该类药物的技术进展进行综述。

Antibody-drug conjugates(ADCs)are new type of drugs that connect antibody and small molecule payload through a linker,and use antibody as carrier to target and transport payload to specific cells.With the launch of the first domestically developed ADC,Disitamab vedotin,ADCs are becoming more widely used in the clinical practice.ClinicalTrial.gov shows 1,685 ongoing clinical trials by February 2022.A total of 14 ADCs have been approved in the worldwide,of which 12 drugs have been approved by FDA,1 by NMPA and 1 by PMPA.After decades of development,the technology for ADCs has been broken through.The design of key ADCs structural elements,such as the antibody,payload,linker,and conjugate technologies,has been developed rapidly in recent years.At the same time,the application of ADCs brings many problems and challenges.To better understand the nature of ADCs,we review the progress of the aforementioned technologies.