編者按：放射性核素偶聯藥物（RDC）正以精準診斷、治療一體化的優勢，成為備受關注的新興偶聯治療模式。多款RDC療法已獲批上市，在提高抗腫瘤活性的同時，減少對正常組織的影響。但與此同時，RDC復雜的分子結構也對工藝開發和生產能力提出了更高要求。作為生物醫藥創新的賦能者，藥明康德依托一體化、端到端的CRDMO平臺，持續支持全球合作伙伴推進包括RDC在內各類偶聯藥物的藥物發現、工藝開發與生產進程。本文將講述藥明康德團隊解決原料供應、工藝優化與雜質控制等難題，助力客戶高效推進RDC項目的案例。

當下，放射性核素偶聯藥物（RDC）正成為腫瘤診療領域備受關注的新方向。RDC巧妙地將精準診斷與靶向治療合二為一，為癌癥患者帶來了全新的治療可能。截至2025年底，全球已有11款RDC藥物獲批上市，持續驗證其臨床療效與潛力。

在廣闊前景的背后，研發挑戰依然存在。RDC藥物結構復雜，由靶向配體（通常是多肽或小分子）、連接子、螯合劑以及放射性同位素共同構成。這些性質各異的“零部件”必須實現精確組裝，對工藝開發和生產能力提出了極高要求。

數年前，一家生物技術公司在開發一款基于環肽的RDC藥物時，就曾深陷這樣的困境。

他們當時在與另一家公司合作，但一年多過去，項目進展緩慢，用于后續開發的關鍵分子遲遲無法交付。

在漫長的等待無果后，客戶將希望寄托在藥明康德身上。

一體化平臺讓項目重新“流動”起來

接手項目后，作為藥明康德旗下專注于寡核苷酸、多肽及相關化學偶聯藥物的一體化CRDMO平臺，WuXi TIDES迅速開展工作。團隊的首要任務，是優化先導化合物結構，助力客戶確認臨床前候選化合物（PCC）。

首先擺在面前的，是原料供應的不確定性。

項目所需的關鍵非天然氨基酸（UAA）外部供應并不穩定，采購周期長，一旦受限很容易拖慢項目進程。

為了避免原料短缺的風險，WuXi TIDES的藥物發現團隊自主開發了該UAA的合成工藝，為項目建立了穩定的UAA供應鏈。

在穩定的原料供應下，WuXi TIDES藥物發現團隊在4個月內交付了兩百多種環肽變體，較客戶期望提前1個月交付，且純度均超過95%。此外，WuXi TIDES藥物發現團隊與藥明康德測試團隊緊密合作，持續優化分子的各項特性，推進在體外和體內檢測中表現良好的先導化合物。最終，在各團隊的攜手合作下，幫助客戶確定了臨床前候選化合物。項目也隨后順利進入工藝開發階段。

在傳統研發模式下，這一階段往往伴隨著重新驗證及信息傳遞不暢帶來的“斷點”。而藥明康德一體化、端到端的CRDMO模式，正好能夠打通這些環節，支持不同團隊間高效協同。

依托這一模式，工藝開發團隊立即從藥物發現團隊接手所有數據和物料，實現項目不同階段的無縫銜接，同時也最大限度地消除了物料多方流轉帶來的交叉污染風險。

進入工藝開發階段后，團隊并沒有滿足于常規合成路徑，而是積極探索新的方向。

按照常規合成思路，多個反應步驟需要依次經過分離、純化、干燥，不僅周期漫長，也意味著每一步操作都有造成物料降解或損失的風險。

針對這一問題，工藝開發團隊提出的思路是：跳過中間的分離步驟。在小分子工藝開發中，這種被稱為“聯投”（telescoping process）的策略應用廣泛，其通過溶液水洗或直接反應將物料投入下一步，從而省去固體分離、過濾、干燥等操作。

依托藥明康德在小分子領域長期積累的工藝開發經驗，團隊很快驗證了聯投策略在RDC體系中的適用性，并將其成功應用于這個項目。

結果令人振奮：聯投策略將合成周期縮短30%，同時原料用量也降低約30%，減少了操作步驟帶來的物料損失。

破解難題，實現高質量交付

另一個貫穿項目始終的挑戰，則是雜質控制。

由于金屬螯合結構的存在，RDC分子在生產和純化過程中不僅與目標核素結合，還容易捕獲環境中的其他金屬。這些意外結合的金屬會形成結構極其相似的雜質，既難分離，也難以精準識別。

對此，WuXi TIDES團隊從項目初期，就將雜質控制納入整體工藝設計。

多個跨學科團隊協同推進，從不同維度拆解這一難題：原料藥研發和分析團隊從分析及純化方法入手，有效區分了結構相似的金屬螯合物和前體，并通過調整溶劑體系和操作、反應條件，盡可能降低外源金屬引入的風險；在更細微的層面上，制劑團隊和分析團隊還對容器和材料進行篩選，進一步減少潛在干擾。

通過這一定制化的雜質控制策略及持續的工藝優化，團隊交付的產品純度提升至99%，總收率提升了超50%。

當首批原料藥順利交付時，客戶激動地表示，這個曾停滯一年多的項目，終于在藥明康德完成了。

項目成功交付后，該客戶又陸續將其他項目交給了藥明康德。一次成功的合作，轉化為持續深化的長期信任。

圖片來源：123RF

如今，WuXi TIDES已建立起覆蓋RDC藥物發現、工藝開發和生產的一體化能力，能夠支持全球客戶高效推進RDC項目。

隨著RDC等新型療法的不斷發展，藥物研發的復雜性正在持續提升。從分子設計到工藝開發，再到生產放大與質量控制，每一個環節都對協同與效率提出了更高要求。

在這樣的背景下，藥明康德的一體化、端到端CRDMO平臺，隨時準備應對更多挑戰。依托于這一全球化賦能平臺，藥明康德持續將全面的能力整合為連貫的開發路徑，在加速開發的同時，降低風險、確保質量，支持全球合作伙伴推進項目進程。

未來，面對越來越多的復雜分子，藥明康德將繼續與全球合作伙伴攜手，將復雜的科學問題轉化為可執行的開發路徑，賦能客戶加速更多創新療法從實驗室走向臨床，早日到達患者手中。

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.

Image source：123RF

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.

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