（来源：学术经纬）

编者按：放射性核素偶联药物（RDC）正以精准诊断、治疗一体化的优势，成为备受关注的新兴偶联治疗模式。多款RDC疗法已获批上市，在提高抗肿瘤活性的同时，减少对正常组织的影响。但与此同时，RDC复杂的分子结构也对工艺开发和生产能力提出了更高要求。作为生物医药创新的赋能者，药明康德依托一体化、端到端的CRDMO平台，持续支持全球合作伙伴推进包括RDC在内各类偶联药物的药物发现、工艺开发与生产进程。本文将讲述药明康德团队解决原料供应、工艺优化与杂质控制等难题，助力客户高效推进RDC项目的案例。

当下，放射性核素偶联药物（RDC）正成为肿瘤诊疗领域备受关注的新方向。RDC巧妙地将精准诊断与靶向治疗合二为一，为癌症患者带来了全新的治疗可能。截至2025年底，全球已有11款RDC药物获批上市，持续验证其临床疗效与潜力。

在广阔前景的背后，研发挑战依然存在。RDC药物结构复杂，由靶向配体（通常是多肽或小分子）、连接子、螯合剂以及放射性同位素共同构成。这些性质各异的“零部件”必须实现精确组装，对工艺开发和生产能力提出了极高要求。

数年前，一家生物技术公司在开发一款基于环肽的RDC药物时，就曾深陷这样的困境。

他们当时在与另一家公司合作，但一年多过去，项目进展缓慢，用于后续开发的关键分子迟迟无法交付。

在漫长的等待无果后，客户将希望寄托在药明康德身上。

一体化平台让项目重新“流动”起来

接手项目后，作为药明康德旗下专注于寡核苷酸、多肽及相关化学偶联药物的一体化CRDMO平台，WuXi TIDES迅速开展工作。团队的首要任务，是优化先导化合物结构，助力客户确认临床前候选化合物（PCC）。

首先摆在面前的，是原料供应的不确定性。

项目所需的关键非天然氨基酸（UAA）外部供应并不稳定，采购周期长，一旦受限很容易拖慢项目进程。

为了避免原料短缺的风险，WuXi TIDES的药物发现团队自主开发了该UAA的合成工艺，为项目建立了稳定的UAA供应链。

在稳定的原料供应下，WuXi TIDES药物发现团队在4个月内交付了两百多种环肽变体，较客户期望提前1个月交付，且纯度均超过95%。此外，WuXi TIDES药物发现团队与药明康德测试团队紧密合作，持续优化分子的各项特性，推进在体外和体内检测中表现良好的先导化合物。最终，在各团队的携手合作下，帮助客户确定了临床前候选化合物。项目也随后顺利进入工艺开发阶段。

在传统研发模式下，这一阶段往往伴随着重新验证及信息传递不畅带来的“断点”。而药明康德一体化、端到端的CRDMO模式，正好能够打通这些环节，支持不同团队间高效协同。

依托这一模式，工艺开发团队立即从药物发现团队接手所有数据和物料，实现项目不同阶段的无缝衔接，同时也最大限度地消除了物料多方流转带来的交叉污染风险。

进入工艺开发阶段后，团队并没有满足于常规合成路径，而是积极探索新的方向。

按照常规合成思路，多个反应步骤需要依次经过分离、纯化、干燥，不仅周期漫长，也意味着每一步操作都有造成物料降解或损失的风险。

针对这一问题，工艺开发团队提出的思路是：跳过中间的分离步骤。在小分子工艺开发中，这种被称为“联投”（telescoping process）的策略应用广泛，其通过溶液水洗或直接反应将物料投入下一步，从而省去固体分离、过滤、干燥等操作。

依托药明康德在小分子领域长期积累的工艺开发经验，团队很快验证了联投策略在RDC体系中的适用性，并将其成功应用于这个项目。

结果令人振奋：联投策略将合成周期缩短30%，同时原料用量也降低约30%，减少了操作步骤带来的物料损失。

破解难题，实现高质量交付

另一个贯穿项目始终的挑战，则是杂质控制。

由于金属螯合结构的存在，RDC分子在生产和纯化过程中不仅与目标核素结合，还容易捕获环境中的其他金属。这些意外结合的金属会形成结构极其相似的杂质，既难分离，也难以精准识别。

对此，WuXi TIDES团队从项目初期，就将杂质控制纳入整体工艺设计。

多个跨学科团队协同推进，从不同维度拆解这一难题：原料药研发和分析团队从分析及纯化方法入手，有效区分了结构相似的金属螯合物和前体，并通过调整溶剂体系和操作、反应条件，尽可能降低外源金属引入的风险；在更细微的层面上，制剂团队和分析团队还对容器和材料进行筛选，进一步减少潜在干扰。

通过这一定制化的杂质控制策略及持续的工艺优化，团队交付的产品纯度提升至99%，总收率提升了超50%。

当首批原料药顺利交付时，客户激动地表示，这个曾停滞一年多的项目，终于在药明康德完成了。

项目成功交付后，该客户又陆续将其他项目交给了药明康德。一次成功的合作，转化为持续深化的长期信任。

如今，WuXi TIDES已建立起覆盖RDC药物发现、工艺开发和生产的一体化能力，能够支持全球客户高效推进RDC项目。

随着RDC等新型疗法的不断发展，药物研发的复杂性正在持续提升。从分子设计到工艺开发，再到生产放大与质量控制，每一个环节都对协同与效率提出了更高要求。

在这样的背景下，药明康德的一体化、端到端CRDMO平台，随时准备应对更多挑战。依托于这一全球化赋能平台，药明康德持续将全面的能力整合为连贯的开发路径，在加速开发的同时，降低风险、确保质量，支持全球合作伙伴推进项目进程。

未来，面对越来越多的复杂分子，药明康德将继续与全球合作伙伴携手，将复杂的科学问题转化为可执行的开发路径，赋能客户加速更多创新疗法从实验室走向临床，早日到达患者手中。

Overcoming Challenges in Developing RDCs: WuXi AppTec’s CRDMO Model

Radionuclide drug conjugates (RDCs) are emerging as a promising conjugate therapeutic modality, offering advantages of integrating precise diagnosis with targeted therapy. Several RDC therapies have been approved, demonstrating improved anti-tumor activity while minimizing side effects on normal tissues. Meanwhile, the complex molecular structure of RDCs places higher demands on process development and manufacturing capabilities. As an enabler of innovation, WuXi AppTec leverages its integrated, end-to-end CRDMO platform to continuously support global partners in advancing research, development and manufacturing of conjugate modalities, including RDCs. This article presents a case study that the team in WuXi AppTec addressed challenges in raw material supply, process optimization, and impurity control to support a client to advance their RDC program.

RDCs have recently emerged as a promising approach in oncology, attracting increasing attention. By integrating precision diagnosis with targeted therapy, RDCs offer a new therapeutic paradigm for cancer patients. As of the end of 2025, 11 RDC drugs have been approved globally, validating their clinical value and potential.

Despite this progress, development challenges remain. An RDC is structurally complex, typically consisting of a targeting ligand (typically a peptide or small molecule), a linker, a chelator, and a radioactive isotope. These components must be precisely assembled, placing high requirements on process development and manufacturing capabilities.

Several years ago, a biotech company encountered such challenges while developing a cyclic peptide-based RDC.

Initially, the biotech was working with another partner. However, after more than a year, the progress remained stalled, and key molecules required for downstream development were not delivered.

After a prolonged delay, the biotech selected WuXi AppTec.

An Integrated Platform Brings the Project Back on Track

Upon taking over the project, WuXi TIDES, WuXi AppTec’s integrated CRDMO platform focused on oligonucleotides, peptides, and related synthetic conjugates, moved swiftly. The team’s immediate priority was to optimize the lead structure to identify a preclinical candidate (PCC).

The initial hurdle was the uncertainty in raw material supply.

A key unnatural amino acid (UAA) required for the project faced unstable external supply and long procurement periods, which posed a risk of delaying progress.

To mitigate this risk, the discovery team at WuXi TIDES developed a synthetic route internally for the UAA, establishing a stable supply chain. 

With a reliable material supply in place, the discovery team delivered more than 200 cyclic peptide variants with over 95% purity within 4 months—one month ahead of the client’s expectation. They worked with WuXi Testing team to refine the molecular properties and advanced lead candidates with optimized in vitro and in vivo profiles. Through the combined efforts of all teams, the client ultimately nominated a preclinical candidate.

Following candidate selection, the project was advanced to the process development stage.

In traditional models, this handoff often leads to inefficiencies due to revalidation and fragmented result exchange. WuXi AppTec’s integrated, end-to-end CRDMO model is designed to eliminate such discontinuities, enabling seamless collaboration across teams.

Leveraging this model, the process development team directly received all related information from the discovery team, ensuring continuity across project stages and reducing contamination risk from cross supplier handovers.

During process development, the team went beyond conventional synthetic approaches and explored alternative strategies.

Traditional approaches require sequential isolation, purification, and drying steps after each reaction, which are time-consuming operations that also incur cumulative material losses.

To address this, the team implemented a telescoping process strategy. Commonly used in small molecule development, telescoping process allows intermediates to proceed directly into subsequent reactions without isolation, through solution-phase transfers or direct carryover. This eliminates the need for solid isolation, filtration, and drying.

Drawing on WuXi AppTec’s extensive experience in small molecule process development, the team quickly validated the applicability of the telescoping process for RDCs and successfully implemented it in this project.

The results were significant: the telescoping process reduced the synthesis cycle by 30% and decreased material usage by approximately 30%, minimizing losses associated with intermediate steps.

Addressing Challenges to Enable High-Quality Delivery

Another key challenge throughout the project was impurity control.

Due to the presence of metal-chelating structures, during production and purification, RDC molecules are capable of binding the intended radionuclide, while also exhibiting affinity for trace metals from the environment. These unintended metal complexes form structurally similar impurities that are difficult to separate and accurately identify.

To address this, WuXi TIDES incorporated impurity control into the overall process design from the outset.

Cross-functional teams collaborated to tackle this issue from different dimensions. The analytical-purification method was developed to distinguish structurally similar metal-chelated species and precursors. The drug substance team optimized solvent systems, operational procedures, and reaction conditions to minimize the introduction of exogenous metals. The formulation and analytical teams also carefully screened containers and materials to further minimize potential interference.

Through project-specific solutions and a series of process optimizations, the crude purity reached 99%, while overall yield increased from 29% to 44%.

When the first batch of API was successfully delivered, the client was excited to see that the project, which had once stalled for over a year at another provider, was completed at WuXi AppTec.

Following the successful delivery, the client subsequently entrusted several additional projects to WuXi AppTec, turning a single collaboration into a long-term partnership built on trust.

Today, WuXi TIDES has established integrated capabilities covering RDC discovery, process development, and manufacturing, enabling global customers to efficiently advance RDC projects.

As emerging modalities such as RDCs continue to evolve, the complexity of drug development is increasing. From molecular design to process development, and from scale-up to quality control, each stage demands higher levels of coordination and efficiency.

With its integrated, end-to-end CRDMO platform, WuXi AppTec combines comprehensive capabilities into a cohesive development pathway to address these challenges and deliver speed, quality and value while advancing programs.

Looking ahead, as increasingly complex molecules emerge, WuXi AppTec will continue to work with global customers to translate scientific challenges into executable development strategies, enabling the acceleration of innovative therapies from the laboratory toward the clinic, and ultimately to patients.