从0.1%到3%！多肽偶联药物产率提升，助力临床试验及时启动

编者按：多肽药物已成为治疗多种疾病的重要手段。目前，全球已有约100款多肽药物获批上市，覆盖糖尿病、肥胖症、癌症及罕见疾病等多个领域，为患者带来了全新的治疗策略。然而，与传统的小分子药物相比，多肽药物更为复杂，涉及非天然氨基酸（UAA）合成、肽库合成、偶联化合物合成、放大生产工艺开发以及制剂开发等多个环节，对专业技术能力提出了更高要求。为更好地满足全球合作伙伴在多肽药物研发方面的需求，药明康德旗下WuXi TIDES围绕多肽药物建立了一体化CRDMO平台，提供包括线性、环状和高度修饰的多肽，以及非天然氨基酸、连接子、毒素和多肽偶联物的合成服务，支持从药物发现、CMC开发到商业化生产的各个阶段。本文将通过一个具体案例，展示WuXi TIDES的一体化平台如何高效推动合作伙伴复杂多肽偶联药物的开发进程。

在该案例中，客户所开发的一款多肽偶联药物结构复杂，由两个短环肽片段和一个长线性多肽组成，合成步骤多达87步。初期合成方案的总体产率不足0.1%，难以满足临床试验的需求。同时，该药物所需的3种UAA原料供应紧张，若从外部采购可能严重延误研发进度。

面对上述挑战，WuXi TIDES团队提出了多项针对性解决方案。针对UAA原料短缺问题，团队充分发挥自身生产UAA的能力，迅速开发出可行的合成工艺，并成功制备了超过3公斤的UAA原料，从源头保障了项目的顺利推进。这一内部合成策略不仅降低了对外部供应商的依赖，还显著优化了进度管理，大幅缩短整体项目周期。

与此同时，WuXi TIDES团队致力于提升多肽合成效率。考虑到传统固相合成方法合成超过50个氨基酸的多肽时，往往面临效率与产率下降的挑战，WuXi TIDES团队采用了“片段合成+化学连接”策略，将目标多肽拆分成多个适合固相合成的小片段，分别合成后再通过化学连接形成完整多肽分子。这一策略将总体产率从不足0.1%提升至3%，并使多个团队能够同时进行片段合成，显著加快了项目推进速度。

在复杂冗长的合成路线中，每一个细节都可能影响最终质量与产率。为进一步优化工艺，WuXi TIDES团队对多个关键步骤的合成和纯化条件进行了反复筛选与优化。在放大生产阶段，团队专门设计了定制的纯化材料，使杂质水平下降80%，最终产率提升20%。得益于UAA合成团队、多肽合成团队和分析团队的高效执行及并行作业，WuXi TIDES团队仅用4个月即完成了工艺开发与优化，7个月内交付了两批各100克的GLP样品，随后又在3个月内顺利生产出1千克GMP级原料药，产率达3%，纯度达97.4%。项目整体进度比合作伙伴预期提前4个月，为临床试验的及时启动提供了强有力保障。

化学合成能力之外，WuXi TIDES还可赋能多肽药物从临床前到商业化阶段的口服和注射制剂的开发和生产。口服制剂平台支持包括片剂、胶囊、脂质体、粉末、颗粒和口服液等各类剂型的开发和生产；注射剂平台则支持多种剂型和灌装形式的无菌制剂生产。展望未来，WuXi TIDES团队将持续依托其一体化CRDMO平台，助力全球合作伙伴充分发挥多肽疗法的巨大潜力，为患者带来更多创新药物。

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.

参考资料：

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

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