8个月提升超50倍！药明康德做对了什么？

编者按：抗体偶联药物（ADC）正以精准靶向与高效杀伤的双重优势，成为肿瘤治疗领域最具潜力的新兴分子类型之一。但随着分子复杂性的增加，ADC的合成愈加艰难，实验室里的巧妙设计常常在放大阶段遭遇瓶颈。在一个合作项目中，一条超过50步的ADC合成路线收率极低。面对客户的难题，药明康德研发化学服务部（Research Chemistry Services，RCS）团队用8个月找到了答案，将总收率提升超50倍，支持项目进入后续工艺放大环节。这个案例的背后，既是多技术平台的协同，也是一种研发思维的转变——从项目伊始，就将“可放大性”写进路线设计的底层逻辑。如需了解药明康德研发化学服务或业务咨询，请点击文末“阅读原文”。

近年来，随着多款ADC药物获批上市，这一领域迅速升温，并不断向更复杂的分子形态演进——例如搭载更复杂的载荷、开发新型连接子、探索双抗ADC等。然而，这些新型分子结构更为复杂，合成路线冗长，副反应控制难度大，对合成与工艺能力提出了极高要求。

几年前，一家药企在推进一个新型ADC项目时，就遭遇了棘手的研发瓶颈。

按项目规划，客户需要在12个月内优化合成路线并完成交付，以推进至后期开发。但现实是，该分子的初始合成路线不仅步骤繁多，还大量依赖复杂的纯化操作，导致整体收率处于极低水平。

这个长路线、高难度的分子合成项目，对化学合成与早期工艺优化能力提出了全面考验。正是在这一背景下，客户将目光投向了药明康德。

面对挑战，药明康德研发化学服务部团队以早期工艺放大为导向进行了初步路线优化。运用多个技术平台的综合能力，团队攻克了副产物控制等关键难题，在8个月内将总收率提升超50倍，以超出客户预期的速度与质量完成交付。

此后，该项目在药明康德内部从早期合成顺利推进至后期工艺开发阶段。此次合作经历也转化为长期的信任纽带，为双方后续在更多管线上的深度合作奠定了基础。

从首个合作项目到长期信任

这一合作并非偶然，而是源于长期积累的深厚信任。

多年前，在双方的一次早期接触中，药明康德RCS团队接手了该客户一个已暂停多年的分子。面对这个久攻不下的项目，团队依托长期积累的药物发现化学能力，重新设计了一条更为简洁的合成路线。

最终，团队用9个月的时间成功破局，将沉睡多年的项目重新激活。这个项目由此成为双方战略合作的起点，也为后续的深度协作筑牢了根基。

正是基于这份在实际项目中建立起的信任，当客户遭遇文章开头的研发瓶颈时，再次想到了药明康德。

当时，乘着ADC分子的发展浪潮，客户正尝试开发一类新型ADC分子。经过前期积累，客户已从多条候选合成路线中筛选出了一条潜力路线。

但现实挑战依然严峻：超过50步的合成反应效率低下，远不足以支持后续的工艺放大。其中，一系列高难度化学反应（例如多片段偶联、副产物控制等）的存在，导致合成路线中的多个中间体副产物比例高、分离困难。这些中间体如同一串精密衔接的齿轮，任何一环的偏差，影响都会传导到最终产物。

破局关键：多平台协同与DPC思维

面对挑战，药明康德团队从早期工艺视角出发，展开了系统性的优化。其中，两个核心能力成为了破局的关键。

其一，是多个技术平台能力的协同支持。彼时，这一领域尚属行业早期探索阶段，鲜有成熟经验可循。而药明康德近年来已经逐步搭建并完善了ADC能力平台。同时，针对合成路线中的关键步骤，团队综合利用催化剂筛选、重结晶等技术平台优化工艺条件与反应路线，系统性提升各步骤的收率与产物纯度。

凭借在该领域的深厚积累，药明康德RCS已经构建了覆盖连接子与载荷合成、分析及纯化的一体化技术平台。依托超过10年的项目经验，平台已累计交付超过27,000种相关化合物，并建立包含1,000余种连接子、30多类抗体连接位点及超过30种新型载荷及其类似物的模块化体系，可支持从毫克级到百克级的灵活合成。

其二，则是贯穿始终的发现工艺化学（Discovery Process Chemistry，DPC）思维。在传统的药物研发中，发现化学与工艺化学往往存在明显的断层：一些在实验室里表现良好的反应，一旦放大就会面临收率骤降、难以重现等问题。

而药明康德遵循的DPC思维，正是为了在发现化学和工艺化学之间搭建桥梁。这一思路要求将“可放大性”前置到药物发现阶段，从项目伊始便以后续的工艺开发为导向。为此，所有路线选择、条件设定不再仅仅追求“拿到产物”，而是充分考虑可转移性与可复制性，从而在早期就为放大生产锁定合适的反应条件。

图片来源：123RF

系统性优化，破解副反应难题

这种全局思维与平台能力，在攻克一道副产物难题时得到了充分验证。

在合成路线中，一个关键的中间体极易发生预期之外的“消除反应”，导致副产物增多。在初始路线中，由于副产物生成较多，不仅造成物料损耗，更给后续的分离纯化和生物测试带来挑战。

针对这一难题，团队依托多平台的综合能力，从多个环节进行系统性优化：

• 路线设计：通过调整分子结构与反应策略，从根源上抑制副反应发生，显著提升目标产物比例。

• 工艺条件：系统筛选偶联反应条件，锁定副产物更少、收益更高的反应窗口。

• 纯化策略：面对传统纯化方式成本高、放大困难的挑战，团队在DPC思维的指引下，引入催化剂筛选、重结晶、流动化学等技术平台，大幅简化操作步骤，在提升纯化效率的同时降低放大难度。

最终，经过多维度的优化，显著抑制了副反应的发生，大幅提升了目标产物的纯度与单步收率，为后续放大扫清了障碍。

8个月，实现超50倍收率提升

这一关键步骤的成功优化，正是整个合成路线系统性重构的缩影。当每个关键节点都被重新打磨后，早期工艺放大就成了水到渠成的事。

在项目的第一阶段，RCS团队在5个月内将总收率提升超5倍，交付量提升也满足了生物筛选测试的需求。

紧随其后的第二阶段，需实现从毫克向克级的放大。团队在前期优化的基础上进一步提速，将预计6个月的周期缩短至3个月，总收率进一步提升超10倍。

两个阶段相加，RCS团队仅用8个月完成了客户的任务目标，总收率相较初始路线提升超50倍，物料使用效率大幅提高。仅仅最后一步，就实现了超5倍的单步收率增长，大幅降低了物料成本的损耗。

最终，项目顺利进入后续工艺放大环节。

此次合作项目的高质量交付，赢得了客户的高度认可。如今，该客户已将更多新型ADC合作项目委托给药明康德团队。

从超50步合成的复杂分子，到与客户持续深入的合作，这个故事的意义早已超越单一项目的交付。当创新疗法越来越复杂，真正稀缺的不只是科学灵感，还有把灵感转化为疗法的能力。这正是药明康德作为生物医药创新赋能者的价值所在。如需了解药明康德研发化学服务或业务咨询，请点击文末“阅读原文”。

An Over 50-Fold Yield Increase in 8 Months: How WuXi AppTec Helped a Client Overcome a Development Bottleneck

Antibody-drug conjugates (ADCs) have emerged as one of the most promising therapeutic modalities in oncology. Yet as molecular designs grow increasingly complex, the synthesis and process development of ADCs are becoming increasingly challenging. WuXi AppTec has established an integrated ADC platform to help clients accelerate ADC development. In one recent case, the team improved the overall yield of a client's innovative ADC molecule over 50-fold in just 8 months, a result that opened the door to deeper, long-term collaboration.

Several years ago, a biopharmaceutical company encountered just such a development bottleneck while advancing an innovative ADC project.

To keep the project on track for later-stage development, the client needed to optimize the synthetic route and complete delivery within 12 months. The initial route, however, involved numerous steps and relied heavily on complex purification processes, resulting in an extremely low overall yield.

This long and technically demanding synthesis posed a comprehensive challenge to both synthetic chemistry and early-stage process optimization. Against this backdrop, the client turned to WuXi AppTec.

To address these challenges, WuXi AppTec’s Research Chemistry Services (RCS) team optimized the route with future scale-up in mind.By integrating capabilities across multiple technology platforms, the team addressed critical challenges including byproduct control and increased the overall yield over 50-fold within just 8 months, delivering with a speed and quality that exceeded the client’s expectations.

The project subsequently progressed smoothly within WuXi AppTec from synthesis into later-stage process development. The experience also further strengthened the relationship between the two organizations, laying the foundation for deeper collaboration across additional pipelines.

How an Initial Collaboration Turned to Long-Term Trust

This collaboration did not happen by chance. It grew out of trust built through years of working together.

During an earlier engagement, the RCS team took on a molecule from the same client that had been stalled for many years. Faced with this long-standing challenge, the team drew on its extensive experience in drug discovery chemistry to redesign the synthesis and develop a more streamlined route.

Within 9 months, the team broke through the development bottleneck and successfully revived the long-dormant project. That experience marked the beginning of a strategic partnership and laid the groundwork for deeper collaboration in the years that followed.

It was this trust, established through successful project execution, that led the client to turn to WuXi AppTec again when it later encountered the development challenge described above.

As ADC innovation accelerated, the client was developing a new type of ADC. Based on preliminary work, the client had selected one promising synthetic route from several candidate pathways.

The technical challenges, however, remained substantial. The route involved more than 50 synthetic steps, with low reaction efficiency, far from sufficient to support subsequent process scale-up. Several technically demanding steps, including multi-fragment couplings and byproduct control, resulted in high levels of byproducts in key intermediates and made separation particularly challenging.

Breaking Through: Multi-Platform Synergy and a DPC Mindset

Faced with these challenges, the WuXi AppTec team took an early-stage process view and began systematically optimizing the route. Two core capabilities proved pivotal in breaking the deadlock.

The first was the coordinated support of multiple technology platforms.

At the time, the field was still in its early stage of development, with few established precedents to follow. Over the preceding years, however, WuXi AppTec had progressively built and refined its ADC capabilities.

For critical synthetic steps, the team also leveraged capabilities such as catalyst screening and recrystallization to optimize reaction conditions and route design, systematically improving both yield and product purity.

Drawing on deep expertise in this field, WuXi AppTec’s RCS provides integrated capabilities spanning linker and payload synthesis, analysis, and purification. Built on more than a decade of project experience, the platform has delivered more than 27,000 related compounds and established a modular system encompassing more than 1,000 linkers, over 30 antibody conjugation sites, and more than 30 novel payloads and their analogs. These capabilities support flexible synthesis from the milligram scale to the hundreds-of-grams scale.

The second capability was the consistent application of a Discovery Process Chemistry (DPC) mindset throughout the project.

In conventional drug development, discovery chemistry and process chemistry can sometimes become disconnected. A reaction that performs well at laboratory scale may experience a sharp decline in yield or become difficult to reproduce once scaled up.

The DPC approach is designed to bridge discovery chemistry and process chemistry by bringing scalability considerations forward into the discovery stage. From the outset, downstream process development informs how routes and reaction conditions are selected.The objective is therefore not simply to “make the product,” but also to ensure that the synthetic route is robust, reproducible, and suitable for subsequent scale-up.This allows suitable reaction conditions for scale-up to be identified earlier.

Image source: 123RF

Systematic Optimization to Overcome a Byproduct Challenge

The value of this holistic process perspective and integrated platform capability became especially clear when the team encountered a critical byproduct issue.

At one point in the synthetic route, a key intermediate was highly prone to an unexpected elimination reaction, generating substantial levels of an unwanted byproduct. In the initial route, substantial byproduct formation occurred, resulting in material loss and complicated downstream separation, purification, and biological testing.

To address the problem, the team systematically optimized several aspects of the process by leveraging capabilities across multiple platforms:

• Route design: By adjusting the molecular structure and reaction strategy, the team suppressed the side reaction at its source and substantially increased the proportion of the desired product.

• Process conditions: The team systematically screened coupling conditions to identify a reaction window that minimized byproduct formation while improving yield.

• Purification strategy: Conventional purification approaches were costly and difficult to scale. Guided by the DPC mindset, the team drew on technology platforms including catalyst screening, recrystallization, and flow chemistry to simplify operations, improve purification efficiency, and reduce the complexity of scale-up.

Following this multi-dimensional optimization, side reactions were significantly suppressed and product purity was substantially improved. The single-step yield increased, clearing the way for subsequent scale-up.

An Over 50-Fold Increase in Overall Yield in 8 Months

The successful optimization of this critical step reflected the broader systematic redesign of the entire synthetic route. Once the major bottlenecks had been addressed, early-stage process scale-up became far more straightforward.

During the first phase of the project, the RCS team increased the overall yield over 5-fold within 5 months, with delivery quantities satisfying the needs of biological screening.

The second phase focused on scaling the process from milligram to gram quantities.Building on the optimization already completed, the team further accelerated execution, shortening an anticipated 6-month timeline to just 3 months while achieving another over 10-fold increase in overall yield.

Across the two phases, the RCS team met the client’s objective in only 8 months. Overall yield increased over 50-fold compared with the initial route, while material utilization improved substantially. In the final key step alone, the single-step yield increased over 5-fold, significantly reducing material loss.

The project then advanced smoothly into subsequent process scale-up.

The high-quality delivery earned strong recognition from the client. Since then, the client has entrusted WuXi AppTec with more innovative ADC collaboration projects.

From a complex molecule requiring more than 50 synthetic steps to an increasingly deep and long-term client partnership, the significance of this story extends beyond the successful delivery of a single project.

As innovative therapies become increasingly complex, what is scarce is not only scientific inspiration, but also the ability to translate that inspiration into viable therapies. This is where WuXi AppTec creates value as an enabler of biopharmaceutical innovation.

At the increasingly complex frontier of novel molecule development, WuXi AppTec continues to strengthen its integrated platform capabilities in step with scientific advances and evolving client needs. Through its integrated enabling platform, WuXi AppTec helps innovators worldwide overcome development bottlenecks, accelerate novel therapies toward key milestones, and ultimately bring them to patients sooner.For more information about WuXi AppTec’s Research Chemistry Services or business collaboration inquiries, please click “Read More” at the end of this article.

Key Takeaways:

• WuXi AppTec’s Research Chemistry Services team increased the overall yield of a client’s innovative ADC molecule over 50-fold in 8 months.

• Leveraging the capabilities of WuXi AppTec’s ADC platform, the team systematically optimized the synthetic route, significantly suppressed side reactions and improved product purity for a critical step.

• WuXi AppTec’s Discovery Process Chemistry (DPC) approach bridges discovery chemistry and process chemistry by incorporating scalability considerations early in development, helping identify robust and reproducible synthetic routes and reaction conditions suitable for subsequent process development.

• At WuXi AppTec’s RCS, the ADC platform has delivered more than 27,000 related compounds and established a modular system encompassing 1,000+ linkers, 30+ antibody conjugation sites, and 30+ novel payloads and their analogs, supporting flexible synthesis from the milligram scale to the hundreds-of-grams scale.

免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

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