目前，抗体偶联药物（ADC）赛道一片繁荣，已成为医药行业公认的“下一个PD-1”。随着近年来生物制药技术的不断进步，ADC药物研发进入了高速发展阶段，尤其在肿瘤治疗领域热度高涨。伴随ADC药物的靶点和适应症的不断扩大，ADC药物正在引领一个靶向治疗新时代。
ADC药物的飞速发展，也催生偶联药物技术领域形成了“万物皆可偶联”的态势——XDC。与传统化疗的大面积杀伤特性不同，靶向肿瘤的载体（Carrier）+诱导多种生物学功能的载荷（Payload）+二者的连接子（Linker）的药物形式让XDC能够精准识别、攻击肿瘤细胞，可使用更少的药物达到更好的治疗效果和更低的毒性。
最初，ADC药物就带来了巨大的市场潜力和应用价值，它作为XDC最典型的模式，也带领了其他靶向分子的研究进展。虽进展喜人，但这类药物在开发过程中仍面临不少挑战。现阶段，国内外有关ADC（或XDC）产品针对CMC部分的正式指导原则极少，由于该药物在选取靶抗原、有效载荷、连接子以及偶联方式等方面各有不同，使其在结构上存在多样性和复杂性，这也决定了其在制造、质量控制中存在诸多挑战。
在制定CMC策略时，需要考虑哪些方面以让ADC IND的申报能够顺利获批？生物药CMC标准的建立和验证，是药物最终获得批准进入生产流通的核心环节，更是各国药政监管的核心。那么，针对不同国家和地区，如何制定CMC策略以支持生物创新药的顺利申报？
带着这些问题，《佰家言》近期采访到专注于新型小分子药物和生物制品领域，为创新药企和生物科技公司提供全球主要市场的真实世界监管、CMC、非临床、临床和GxP专业咨询服务的法规监管咨询服务公司DataRevive(德顺达)全球总裁&前FDA CDER OBP审评主管Michele K. Dougherty博士，与她就相关问题进行了一次对话。

Q1
您如何看待目前全球ADC领域的发展趋势？中国企业在ADC研发方面有优势吗？
Michele K. Dougherty:
抗体偶联药物（ADCs）是一类独特的药物形式，它将抗体的特异靶向性和化疗药物的细胞毒性结合在了一起。由于ADC为临床治疗方案提供了单药治疗或与其他抗癌药物联合治疗的另一种选择，越来越多的ADC产品出现在许多生物制药公司的开发管线中。此外，诸如Enhertu和Trodelvy等第三代ADC药物在临床上取得的成功疗效，进一步推动了人们对ADC技术的兴趣和投资热情，同时也带动了ADC药物市场的蓬勃发展，并促使许多生物制药公司自主投入ADC产品研发，或与授权合作伙伴一起共同开发ADC产品。
中国已成为ADC市场格局中极富前景的重要参与者之一。中国公司在全球市场，或与欧美大型制药公司合作方面具有以下多个优势：
1）具有成本效益的研发项目使公司能够高效和有效地配置资源，从而提升资源利用率；
2）涵盖小分子药物和抗体生产的全流程制备能力优化了生产过程，并能显著降低生产成本；
3）相对灵活的监管环境有助于ADC候选药物在临床试验中的顺利推进；
4）中国不断增长的肿瘤药物需求为ADC提供了重要的市场机遇。
通过与像DataRevive公司这样强大的监管合作伙伴的密切合作，生物制药公司可以更从容地应对复杂的监管环境，并通过实施基于科学和风险的开发战略，加速ADC项目的研发进展。
Antibody drug conjugates (ADCs) are a unique class of drug products as they combine the specificity of the targeting antibody with the cytoxicity of the chemotherapeutic.ADCs are increasingly present in development pipelines,as they offer treatment options as monotherapies or in combination with other anti-cancer drugs.Third generation ADC drugs,such as Enhertu and Trodelvy, have demonstrated remarkable clinical success,further driving interest and investment in ADC technology.This success has resulted in a market for ADC drugs,with numerous companies developing their own product or co-developing products with licensing partners. 
China has emerged as a promising player in the ADC development landscape.Chinese companies provide several advantages in the global market and in their potential for partnerships with big pharmaceutical companies in Western countries:1) cost effective R&D programs enable companies to allocate resources efficiently and effectively,2) full capacity of small molecule and antibody manufacturing allows for streamlined production processes and potentially lower production costs,3) a relatively flexible regulatory environment facilitates the advancement of ADC candidates through clinical trials,and 4) the growing demands of cancer drugs in China presents a significant market opportunity for ADCs.
Close collaboration with a strong regulatory partner,such as a firm like DataRevive,helps biotech companies navigate a complex regulatory landscape and enables acceleration of ADC development programs by implementing science- and risk-based development strategies. 
Q2
ADC包含抗体、连接子、有效载荷部分，相较于传统的小分子化药与单克隆抗体，更为复杂。请问在ADC IND的申报中，CMC方面有哪些挑战和注意点？
Michele K. Dougherty:
ADC的制备必须综合考虑单克隆抗体、有效载荷和连接子的各个组份的制备过程。申请方需要提供各个关键组份的数据和信息用来证明ADC的质量。
抗体和连接子-有效载荷是ADC生产过程的关键中间体，它们的生产必须符合GMP的相关要求。最终ADC原料药和后续制剂的制备过程也会引入使质量和安全控制变得复杂的额外因素。
单克隆抗体和抗体-偶联原料药需要进行表征，任何抗体中间体与原料药之间可能存在的产品质量差异都应做出充分解释。例如，在药品中可能观察到电荷分布差异时，应对差异进行表征或适当描述，并控制这些电荷变化。
结合试验可评估在连接有效载荷后抗体的靶向功能是否保持不变，基于细胞的活性检测也是ADC质量控制的重要关键策略之一。此外，DAR和杂质情况需要进行表征和控制，后续临床试验的开展也需要有合适的评估ADC靶向性及细胞毒性功能的活性检测方法。
Considerations for the manufacture of ADCs must take into account processes to manufacture the monoclonal antibody,payload and linker. A sponsor will need to provide data and information to demonstrate the quality of each critical component of an ADC.The antibody and the linker-payload are critical intermediates that must meet applicable GMP requirements for their manufacture.Manufacture of the final ADC drug substance and subsequent drug product introduces additional complexities related to quality and safety.
Characterization of both the monoclonal antibody and the conjugated antibody (drug substance) must be performed.Any differences in product quality between the antibody intermediate and the drug substance should be justified. For example, differences in charge profiles may be observed in the drug substance and charge variants should be appropriately characterized or explained and controlled.The targeting function of the antibody must be maintained following conjugation of the payload,this can be assessed with a binding assay.A cell-based potency assay is an important aspect of the control strategy for an ADC as well.The drug:antibody ratio must be characterized and controlled,impurities should be controlled,and appropriate potency assays that assess the targeting and cytotoxic function of the ADC are needed for clinical development.   
Q3
在生物创新药领域，中国与美国新药IND申报的CMC有哪些异同点？为了走向全球市场，中国公司在哪些方面应更审慎对待？
Michele K. Dougherty:
中国作为国际人用药品注册技术协调会（ICH）成员之一，在中美提交CMC模块时内容将保持一致。针对生物制品而言，外源性杂质和病毒安全性是需要重点控制的因素，特别是在某地进行临床试验并寻求上市批准时，生产制造商应尽力满足该地区最严格的监管要求。
工艺开发和理解是药企实施严格控制策略的关键前提。在准备申报资料时，任何细节都十分关键，因为这往往是申请方与卫生监管部门互动沟通的初次照面，象征着公司对整个产品质量所做出的承诺。
China is part of the International Conference of Harmonization so content of CMC modules for US and China submissions continue to align.For biologic products,ensuring adventitious agent and viral safety of products is an important consideration and manufacturers should strive to meet the most stringent requirements where they would conduct clinical development and seek marketing approval.Process development and understanding will be critical to achieving a rigorous control strategy.Attention to detail in preparation of regulatory dossiers is of critical importance as these are generally the first opportunity a sponsor has to interact with the health authority team and signals a company’s commitment to a quality culture across their entire organization. 
Q4
近年来，中国有很多成功的ADC license out项目，您认为他们获得青睐的因素有哪些？
Michele K. Dougherty:
中国制药公司与国外制药公司在ADC领域日益增长的合作关系是一个值得注意的趋势，预计未来这种合作还将继续发展。近年来，在连接子-载荷稳定性、治疗窗口期和毒性特征等方面的重大技术进步，使得ADC产品的开发展现了越来越大的吸引力。诸如辉瑞收购Seagen以及默克和科伦博泰的重磅交易，都体现出ADC领域的增长潜力和业界对其日益浓厚的兴趣。中国制药公司在包括连接子技术和ADC制造工艺等方面的进步，显著缩短了从临床前阶段到首次人体试验所需的时间，提高了成本效益。这些都体现了中国生物技术公司在ADC平台开发方面的创新能力及运营成本优势。
一般来说，在研管线成功对外授权，很大程度上取决于产品和数据包，那些在非临床和早期临床结果中数据优异的产品更有可能吸引到优秀合作伙伴。此外，产品开发中的CMC控制也很重要。合作伙伴都希望投资的产品能够获得成功，因此，在CMC方面的投入和前瞻性是至关重要的，这可以确保公司在提交上市申请时产品符合商业化生产所需的cGMP和合规标准。
The growing partnership between Chinese and Western companies in the ADC field is indeed a notable trend that is expected to continue in the near future. In recent years,significant technical advancements have addressed some of the concerns surrounding linker-payload stability, therapeutic window,and toxicity profiles,making them more attractive for further development. Notable examples include Pfizer’s acquisition of Seagen and Meck’s deal with Kelun,which demonstrate the increasing interest and growth potential in the field.Chinese biotech companies offer operational and cost advantages,along with their innovation in ADC platform development.This includes advancements in linker technologies and ADC manufacturing processes. These innovations have contributed to significantly shorter timelines and cost-effective development from preclinical stages to first-in-human trials. 
In general,the success of out-licensing is largely dependent on the product and the data package.Products that show promising nonclinical and early clinical results are more likely to be successful in attracting a good partner. In addition,the CMC development program is also important.Partners want to invest in a successful product,so,it is important that the CMC package is sufficiently well developed and forward-looking to ensure confidence that the company will be in a state of readiness for commercial production from a CGMP and compliance perspective by the time the license application is submitted.
Q5
对于创新药企来说，中国药企在整个药物研发的生命周期里该如何制定CMC策略支持新药的顺利“出海”？其中关键点有哪些？
Michele K. Dougherty:
制定任何一个产品的开发计划，制药公司都应尽可能多地考虑将来会寻求上市批准的所有地区，并了解不同地区监管的差异。尽早做好规划，将确保开发过程和CMC控制策略能够实现在全球范围内被认可的目标。此外，药企还必须综合考虑可能影响产品质量的任何因素，以确保临床研究在不同地区的顺利进行，以及临床数据在不同监管地区得到认可。
如何制定CMC策略，制药公司需要考虑以下几个问题：
为商业生产做好充分准备：确保建立完善的质量管理体系，并使制造工厂建立起强大且完善的质量文化；
工艺开发和生产规模：确保生产规模与潜在市场需求一致，并且在提交上市申请之前对工艺进行充分的表征，以实现工艺开发和生产规模相匹配；
原材料控制：原材料的采购应符合最严格的法规要求，并在适当情况下遵循国际认可的药典质量标准，如美国、日本或欧洲药典；
符合药典规定的检测和分析方法：在选择用于放行、稳定性或外源性物质检测的药典方法时，应优先考虑最为严格和规范的药典标准，以确保结果能够被监管地区所接受。
For any development program, a manufacturer should consider all regions where they may pursue marketing approval and understand differences in regulatory requirements.Planning early will ensure that a process and control strategy can be achieved that will be accepted globally. It will also be important to consider other factors that can impact product quality to ensure that clinical studies and clinical data will be accepted in different regulatory regions. 
Some of the issues companies should consider:
  • Readiness for commercial manufacturing–that is,ensuring that robust quality systems are in place and that sites have developed a strong quality culture.
  • Process development and manufacturing scale–that is,ensuring that the scale of manufacturing is consistent with the potential market and that the process has been well-characterized prior to the license application.
  • Raw material control–raw materials should be sourced to meet the most stringent regulatory requirements and,where appropriate,should meet the quality standards of an internationally recognized pharmacopeia,such as the US,Japanese or European pharmacopeia.
  • Compendial methods–when compendial methods are chosen for release,stability or adventitious agent testing the most stringent compendia should be chosen to ensure that results are acceptable across regulatory regions. 
Q6
您怎么看待日新月异的药物形式的发展？例如在ADC之外，各种XDC也发展迅速。
Michele K. Dougherty:
医药行业在应对COVID疫情时的表现表明，先验知识和创新有助于加速药物的开发过程。从针对COVID-19开发药物中获得的提高效率的经验也适用于未来新型药物的研究与开发。然而，医药行业还需要协调好如人力资源等多方面的资源管理，以实现更快速的发展。
The industry’s response to the Covid pandemic demonstrated how prior knowledge and innovation can be used to accelerate drug development.Some of the efficiencies gained from the experience of developing drugs targeting Covid 19 are applicable to novel drug development going forward.However, the industry will need to manage a rapid pace of development against other resources,including their human capital.
Q7
中国有众多CRO公司，你认为DataRevive的竞争优势是什么？除了ADC产品之外，DataRevive(德顺达)的法规监管咨询服务目前还在哪些产品领域发力？
Michele K. Dougherty:
作为Validant集团的成员企业，DataRevive（德顺达）提供从临床前开发到产品生命全周期的全程监管和合规支持服务。我们与Validant姐妹公司携手，拥有一支优秀的由前美国FDA和业界领军翘楚组成的团队，为客户提供战略性监管建议，协助加速临床开发计划，并构建符合cGMP标准的强大质量体系和制造流程，以及支持与全球各地监管机构进行沟通交流。
DataRevive专注于为小分子药物和生物制品（包括单克隆抗体、细胞和基因治疗产品以及疫苗）提供战略性监管咨询并准备监管文件。DataRevive专精于梳理临床开发阶段的数据信息，高效转化为符合监管机构标准的申报资料，用于临床试验和上市的审批申请，助力客户加速产品开发及上市进程。
DataRevive, as a member of the Validant Group, is a resource for regulatory and compliance support from pre-clinical development throughout the product lifecycle. Together with our partner companies, DataRevive offers a distinguished roster of former US FDA and biotech and pharma leaders that can provide strategic regulatory advice, assist with accelerated clinical development programs, build strong quality systems and CGMP compliant manufacturing and support interaction with regulators across the globe. DataRevive specializes in strategic regulatory consulting and preparing regulatory dossiers for both small molecule and biologic products including monoclonal antibodies,cell and gene therapy products and vaccines. DataRevive excels at translating the data and information collected during clinical development into successful regulatory submissions, helping our clients meet their development and organizational goals. 
2023第二届ADC及偶联药全球创新峰会将于9月21-22日江苏无锡召开！XDC2023组委会联合佰傲谷BioValley特别策划「佰家言—让创新药不被定义」专栏。本文为该专栏的第三篇专访报道。
系列阅读：
●佰家言专访药明合联CEO李锦才博士：坚持对解决行业痛点的极致追求，药明合联持续赋能全球XDC行业发展
●佰家言 | 同宜医药创始人黄保华博士：打造Bi-XDC技术平台，做“不可成药”的破局者
Global XDC 2023
主办单位：无锡高新区管委会、药明生物、药明合联、佰傲谷BioValley
支持单位：映恩生物、启德医药、同宜医药、多禧生物、宜联生物、乐普生物、“科创中国”生物医药产业科技服务团、美国华人生物医药科技协会（CBA）
大会时间：2023年9月21-22日
大会地点：中国·无锡
会前活动：9月20日 药明合联新商业化厂房投产庆典
同期活动：9月21日 高端领袖闭门会、高端领袖嘉宾晚宴
本次大会围绕“让创新药不被定义”的主旨，特设Global ADC&XDC、ADC药物研发与临床、偶联药物新组合、新型偶联药物CMC与商业化三大主题专场。DataRevive德顺达全球总裁/前FDA CDER OBP审计主管Michele K. Dougherty博士将出席本次大会，并作“Manufacturing Antibody Drug Conjugates: A Regulatory Roadmap for Success”主题报告。
报名参会（需审核）
 XDC 2023 推荐阅读 
国际生命科学大咖齐聚无锡，探讨“X”无限可能 | Global XDC 2023
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