同行致遠 | 從0.1%到3%！產率提升的背后，是怎樣的一體化實力？| Bilingual

編者按：多肽藥物已成為治療多種疾病的重要手段。目前，全球已有約100款多肽藥物獲批上市，覆蓋糖尿病、肥胖癥、癌癥及罕見疾病等多個領域，為患者帶來了全新的治療策略。然而與傳統的小分子藥物相比，多肽藥物更為復雜，涉及非天然氨基酸（UAA）合成、肽庫合成、偶聯化合物合成、放大生產工藝開發以及制劑開發等多個環節，對專業技術能力提出了更高要求。為更好地滿足全球合作伙伴在多肽藥物研發方面的需求，藥明康德旗下WuXi TIDES圍繞多肽藥物建立了一體化CRDMO平臺，提供包括線性、環狀和高度修飾的多肽，以及非天然氨基酸、連接子、毒素和多肽偶聯物的合成服務，支持從藥物發現、CMC開發到商業化生產的各個階段。本文將通過一個具體案例，展示WuXi TIDES的一體化平臺如何高效推動合作伙伴復雜多肽偶聯藥物的開發進程。

在該案例中，客戶所開發的一款多肽偶聯藥物結構復雜，由兩個短環肽片段和一個長線性多肽組成，合成步驟多達87步。初期合成方案的總體產率不足0.1%，難以滿足臨床試驗的需求。同時，該藥物所需的3種UAA原料供應緊張，若從外部采購可能嚴重延誤研發進度。

面對上述挑戰，WuXi TIDES團隊提出了多項針對性解決方案。針對UAA原料短缺問題，團隊充分發揮自身生產UAA的能力，迅速開發出可行的合成工藝，并成功制備了超過3公斤的UAA原料，從源頭保障了項目的順利推進。這一內部合成策略不僅降低了對外部供應商的依賴，還顯著優化了進度管理，大幅縮短整體項目周期。

與此同時，WuXi TIDES團隊致力于提升多肽合成效率。考慮到傳統固相合成方法合成超過50個氨基酸的多肽時，往往面臨效率與產率下降的挑戰，WuXi TIDES團隊采用了“片段合成+化學連接”策略，將目標多肽拆分成多個適合固相合成的小片段，分別合成后再通過化學連接形成完整多肽分子。這一策略將總體產率從不足0.1%提升至3%，并使多個團隊能夠同時進行片段合成，顯著加快了項目推進速度。

在復雜冗長的合成路線中，每一個細節都可能影響最終質量與產率。為進一步優化工藝，WuXi TIDES團隊對多個關鍵步驟的合成和純化條件進行了反復篩選與優化。在放大生產階段，團隊專門設計了定制的純化材料，使雜質水平下降80%，最終產率提升20%。得益于UAA合成團隊、多肽合成團隊和分析團隊的高效執行及并行作業，WuXi TIDES團隊僅用4個月即完成了工藝開發與優化，7個月內交付了兩批各100克的GLP樣品，隨后又在3個月內順利生產出1千克GMP級原料藥，產率達3%，純度達97.4%。項目整體進度比合作伙伴預期提前4個月，為臨床試驗的及時啟動提供了強有力保障。

化學合成能力之外，WuXi TIDES還可賦能多肽藥物從臨床前到商業化階段的口服和注射制劑的開發和生產。口服制劑平臺支持包括片劑、膠囊、脂質體、粉末、顆粒和口服液等各類劑型的開發和生產；注射劑平臺則支持多種劑型和灌裝形式的無菌制劑生產。展望未來，WuXi TIDES團隊將持續依托其一體化CRDMO平臺，助力全球合作伙伴充分發揮多肽療法的巨大潛力，為患者帶來更多創新藥物。

CRDMO: Integrated Platform Accelerates Complex Peptide Drug Conjugate Development

Peptide drugs have emerged as an important therapeutic modality for a broad spectrum of diseases. To date, approximately 100 peptide-based medicines have received global regulatory approval, providing new treatment options for conditions such as diabetes, obesity, cancer, and rare diseases. However, compared to traditional small molecule drugs, peptides present greater structural complexity. Their development requires advanced capabilities in areas such as unnatural amino acid (UAA) synthesis, peptide library design, conjugation chemistry, scale-up process development, and formulation support. To address these challenges and better support global partners, WuXi TIDES, an integral part of WuXi AppTec, has established an integrated CRDMO platform. The platform offers comprehensive synthesis services for linear, cyclic, and highly modified peptides, as well as UAAs, linkers, payloads, and peptide conjugates. Covering the full development spectrum from drug discovery and CMC development to commercial-scale manufacturing, the platform enables efficient and flexible solutions tailored to each stage of the pipeline.

A recent case study highlights how WuXi TIDES' integrated capabilities expedited the development of a complex peptide conjugate for a global partner. The candidate molecule comprised two short cyclic peptide fragments and one long linear peptide, requiring a highly intricate synthesis of up to 87 steps. The initial synthetic route yielded less than 0.1% overall, insufficient to meet clinical trial demands. Additionally, the project was hampered by the limited availability of three critical UAAs, with external sourcing posing a risk of significant delays.

To overcome these obstacles, the WuXi TIDES team implemented several targeted solutions. First, the team addressed the UAA supply bottleneck by leveraging its internal UAA synthesis capabilities. They quickly developed viable synthetic pathways and produced over 3 kilograms of UAAs, securing raw material availability and safeguarding project timelines. This internal manufacturing strategy not only reduced dependency on external suppliers but also significantly improved timeline control and shortened the overall project duration.

Concurrently, efforts were directed at improving the efficiency of peptide synthesis. Given the challenges of efficiency and yield declines when traditional solid-phase peptide synthesis (SPPS) techniques are used for sequencing longer than 50 amino acids, the WuXi TIDES team adopted a "fragment synthesis + chemical ligation" strategy—breaking down the target peptide into shorter fragments suitable for SPPS, synthesizing them individually, and then linking them chemically into the full-length peptide. This approach improved the overall yield from under 0.1% to 3%, while enabling multiple teams to work in parallel, significantly accelerating development timelines.

Given the complexity and length of the synthesis route, process optimization was critical. The WuXi TIDES team conducted extensive rounds of screening and refinement for key synthesis and purification steps. During scale-up, the team introduced customized purification materials that reduced impurity levels by 80% and improved yield by 20%. Through efficient execution and parallel activities between the UAA synthesis, peptide synthesis, and analytical teams, process development and optimization were completed in just four months. The WuXi TIDES team delivered two batches of 100 grams of GLP-grade material within seven months, followed by the production of 1 kilogram of GMP-grade API in an additional three months. The final process achieved a 3% yield with 97.4% purity. Overall, the project was completed four months ahead of schedule, ensuring timely clinical trial initiation with a secure and robust supply.

Beyond peptide API synthesis, WuXi TIDES also supports both oral and parenteral drug product development and manufacturing for peptide drugs from preclinical to commercial stages. The oral solid platform supports a diverse array of dosage forms such as tablets, capsules, lipid formulations, powders, granules, and liquid-in-bottle, while the parenteral dosage platform accommodates various injectable drug forms and filling formats.

Looking forward, the WuXi TIDES team will continue to leverage its integrated CRDMO platform to accelerate the development of peptide therapeutics. By enabling global partners to unlock the full potential of peptide drugs, WuXi TIDES is helping bring more innovative medicines to patients around the world.

參考資料：

[1] From Discovery to Phase I, Rapid Delivery of a Complex Peptide Conjugate in 10 Months. Retrieved July 28, 2025, from https://tides.wuxiapptec.com/wp-content/uploads/2024/09/cyclic-peptide-conjugate-case-study.pdf

[2] 制劑. Retrieved July 28, 2025, from https://tides.wuxiapptec.com/cn/services-solutions/peptide/peptide-cmc/drug-product/

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