摘要：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，为糖尿病、肥胖症、癌症和罕见疾病等多个领域带来了新的治疗策略。FDA自2001年以来批准的超过40款多肽新药中，过半在近10年内获批，显示了这一领域加速发展的趋势。药明康德旗下Wu
转自：药明康德
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，为糖尿病、肥胖症、癌症和罕见疾病等多个领域带来了新的治疗策略。FDA自2001年以来批准的超过40款多肽新药中，过半在近10年内获批，显示了这一领域加速发展的趋势。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。本文将通过两款多肽疗法的发现和开发案例，展示这一赋能平台如何帮助合作伙伴有效克服多肽药物研发中的多种挑战。
多肽药物有环肽、线性肽、修饰肽等不同类别。虽然与线性肽相比，环肽的代谢稳定性和渗透能力有所提高，然而它们仍然需要通过多肽骨架的修饰和环化策略的优化，进一步提升药物特征。此外，与传统的小分子药物相比，环肽药物更为复杂，需要满足诸如非天然氨基酸合成、肽库合成、偶联化合物合成、放大生产工艺研发以及多肽制剂开发等方面的多种需求。因此，临床阶段的生物技术公司往往需要与专业赋能平台合作，这也正是本文中案例公司选择WuXi TIDES的原因。
以精准的解决方案完成复杂双环肽放大生产
这家公司的在研药物是一款带有偶联糖基侧链的双环肽，起始合成路线需要先分别合成双环肽和侧链，然后再将两者进行化学偶联。然而，双环肽原始合成路线中部分步骤产生的中间产物溶解性很低，不仅大幅度降低了总产率，更使后续反应难以顺利进行，为放大生产带来了极大挑战。此外，为提高最终产物的纯度和产率，在双环肽与侧链偶联之前需增加额外的纯化步骤。整个生产流程对团队的固相和液相合成能力，以及产物的分离和纯化能力都提出了极高要求。
针对这些挑战，WuXi TIDES团队制定了针对性的解决方案。通过优化合成路线并调整反应溶剂，显著提高了中间产物的溶解性，为后续放大生产奠定了基础。同时，负责分离和纯化的团队根据该双环肽设计了量身定制的纯化方案。团队在短短6周内完成了放大生产的工艺优化，并通过一次15 g的小型合成实验验证了新工艺的可行性。
在这个项目中，合作伙伴要求生产两批具有不同盐型的候选化合物用于药物制剂的开发。药物的盐型直接影响溶解度、稳定性、生物利用度、放大生产以及储存等多个方面，因此制剂开发过程对盐型参数提出了严格要求。依托药明康德一体化赋能平台的优势，早在工艺优化过程中，公司的多肽研发与制剂团队就进行了紧密沟通与协作，确保工艺优化后合成的产品满足制剂开发团队的需求，这样的无缝衔接进一步缩短了项目开发时间。
在最终产物的纯化阶段，团队进一步优化纯化工艺，不仅提高了每次处理粗样品的能力，还将单次纯化时间压缩到不到60分钟。经过一系列高效的工艺优化，团队在4个月内顺利完成了两批分别为400克和500克的不同盐型候选化合物的生产，比合作伙伴的预期提前了整整一个月。
上面仅是WuXi TIDES多肽平台助力复杂多肽开发的一个典型案例。团队拥有丰富的复杂肽合成经验，在环化策略上，可采用多种策略合成双环肽和三环肽，包括单/双/三硫醚键环化、硫硫键环化、点击环化、内酯环化、内酰胺环化和烯烃复分解环化等；在合成能力上，具备N-烷基取代、骨架修饰、残基插入和非标准连接子合成等专业能力，有效支持多肽药物的结构活性探索。
WuXi TIDES不仅在复杂多肽生产方面具备加速推动合作伙伴项目开发的硬实力，药明康德一体化CRDMO平台中多个团队间的高效协同合作，在接下来口服环肽的发现和开发案例中，在多个关键节点为缩短项目开发时间、攻克技术挑战发挥了重要作用。
从发现到开发，一体化平台为合作伙伴“抢时间、争速度”
2023年，一家仅有20余名员工的创新生物技术公司发现了一条具有潜在减重效果的信号通路，希望开发口服多肽减重疗法。但该公司缺乏大规模多肽化合物库的生产能力，因此选择与WuXi TIDES展开合作。
在药物发现早期阶段，WuXi TIDES团队根据客户需求，共生产出包括超过1700种不同结构环肽的多肽化合物库，每种化合物纯度均超过95%；并在环肽化合物中引入了多样化侧链突变，应用多种环化策略生成环肽结构，实现了广泛的化学空间探索，帮助客户快速确定最具潜力的候选化合物。
除了药物发现阶段的筛选和确认，口服多肽开发的另一个关键挑战是候选化合物生产规模的放大。由于口服多肽的生物利用度有限，在动物实验阶段的用量与注射型多肽相比要高出数十甚至上百倍，给化合物的及时生产提出了更高要求。
在客户与WuXi Biology团队协作进行药物代谢与药代动力学（DMPK）和药效学动物实验期间，WuXi TIDES负责研究阶段多肽合成的团队与WuXi Biology负责筛选的团队紧密配合，加快了检测数据的收集、反馈以及设计上的优化，同时在两周内就完成平均批次50克的候选化合物生产。
合作伙伴对双方的合作及成果表示非常满意，对于WuXi TIDES团队表现出来的科学专业能力与高效执行给予了高度认可，这些能力使项目加速推进成为可能。基于对团队的信任，该公司在药物发现阶段结束后决定继续与WuXi TIDES合作，推进后续药物开发研究。
将候选化合物从发现阶段推进到开发阶段，是新药研发过程中的重要分水岭。开发阶段的药物生产流程需遵守更加严格的监管要求，如GLP和GMP标准。若在此阶段更换生产厂商，技术交接过程可能导致项目延误。然而在药明康德，WuXi TIDES的一体化CRDMO服务平台拥有同时支持发现和开发两个阶段的研发及生产能力。在这一项目中，负责CMC业务的多肽工艺团队提前布局，在候选化合物仍处于发现阶段时即启动前期准备和技术交接工作。因此，当客户决定启动开发阶段工作时，仅用1天时间就完成了合成工艺与分析方法的转移及物料准备，实现了两阶段之间的无缝衔接，迅速进入了工艺优化环节。
在工艺优化过程中，团队快速评估了8种不同的合成条件，使粗肽的纯度提高15%；同时通过纯化工艺的改进，使纯化收率大于90%。最终在短短6周内顺利完成了第一批1公斤GLP级别多肽候选化合物的生产交付。
在进行首批生产的同时，团队已着手启动第二轮工艺优化，以进一步满足更大规模生产的需求。在随后的一个半月内，团队完成了4条生产路线的评估和优化，并成功将一种复杂UAA砌块替换为一种更常见、更易获取的UAA原料，这一调整不仅降低了原材料的采购难度和周期，也大幅度降低了生产成本。通过对固相合成工艺的持续优化，与首批1公斤样本生产相比，粗肽纯度进一步提升超30%，最终收率提升50%。
在客户决定启动毒理学研究时，为团队设定了极为急迫的交付时间线。得益于一体化CRDMO平台中多个团队的协作，WuXi TIDES团队在候选多肽化合物生产尚未完成时，便与负责生产、质量控制（QC）和物流管理的各团队制定了详尽的时间表，以确保后续工作迅速且有序地进行。最终，团队在7周内成功完成第二批6公斤GLP级别候选药物的生产，充分保障了合作伙伴能够按计划顺利展开毒理研究。从候选化合物优化到GMP生产准备完成，用时不到12个月。
全面赋能多肽药物开发
近期《自然》旗下Signal Transduction and Targeted Therapy期刊发表的一篇综述显示，截至2024年底，已有近40款多肽疗法已进入3期临床阶段，覆盖糖尿病、罕见病、传染病、眼科疾病、癌症等多个治疗领域。
与此同时，将不同功能载荷偶联在多肽上构成的多肽偶联药物也成为产业兴起的新热点。目前已有超过30款多肽偶联药物入临床开发阶段，与多肽偶联的载荷涵盖细胞毒性分子（PDC）、放射性药物（RDC）、以及复杂的寡核苷酸药物（如POC、PPMO）等多种类型。WuXi TIDES在这一快速发展的领域也早已进行了战略布局，配备有包括寡核苷酸、多肽、单体、配体、连接子、脂质等在内的“一站式”技术平台，拥有丰富的化学合成经验，广泛覆盖各种单体、配体、连接子及脂质类型，可以满足来自不同客户、不同分子类型、不同偶联位置、不同载荷的差异化需求，全面助力合作伙伴更好地实现新药研发梦想。
近年来，WuXi TIDES也在持续推进多肽产能建设，预计2025三季度多肽固相合成反应釜总体积将提升至10万升以上。展望未来，团队将继续助力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疗法和高质量药物。
CRDMO: Empowering the Future of Peptide Therapeutics
Peptide-based therapeutics have emerged as a vital treatment modality for a broad spectrum of diseases. To date, approximately 100 peptide drugs have been approved worldwide, offering new therapeutic options for conditions such as diabetes, obesity, cancer, and rare diseases. WuXi TIDES, part of WuXi AppTec, has established an integrated CRDMO platform dedicated to peptide therapeutics. This platform provides synthesis capabilities for linear, cyclic, and highly modified peptides, as well as for non-natural amino acids, linkers, toxins, and peptide-drug conjugates. It supports all stages of development, from drug discovery and CMC development to commercial-scale manufacturing. This article presents two case studies that illustrate how the WuXi TIDES platform empowers partners to overcome critical challenges in peptide drug development.
Peptide drugs come in various formats, including cyclic peptides, linear peptides, and structurally modified peptides. Compared to linear peptides, cyclic peptides typically exhibit improved metabolic stability and membrane permeability. However, developing cyclic peptides still requires advanced optimization of backbone structures and cyclization strategies to enhance their drug-like properties. In addition, these molecules are inherently more complex than traditional small molecules, often requiring capabilities such as non-natural amino acid synthesis, peptide library design, conjugation chemistry, scale-up process development, and formulation support. For this reason, clinical-stage biotech companies often collaborate with experienced CRDMO partners—one of the key reasons the companies featured here chose WuXi TIDES.
Delivering Complex Bicyclic Peptide Scale-Up with Tailored Solutions
One case involved a company developing a bicyclic peptide drug candidate with a conjugated glycosylated side chain. The initial synthetic route required separate synthesis of the peptide core and the side chain, followed by chemical conjugation. However, certain steps in the original synthesis produced intermediates with poor solubility, significantly reducing overall yield and hindering downstream reactions—creating challenges for scale-up. To further improve product purity and yield, an additional purification step was required prior to conjugation. The overall manufacturing process placed high demands on the team’s capabilities in both solid- and solution-phase peptide synthesis, as well as in separation and purification techniques.
To overcome these challenges, the WuXi TIDES team developed a customized solution. By optimizing the synthesis route and adjusting reaction solvents, they significantly improved intermediate solubility, laying the groundwork for successful scale-up. The purification team also designed a tailored purification protocol specific to the bicyclic peptide structure. Within just six weeks, the team completed process optimization and validated the new route through a 15-gram pilot synthesis.
In this project, the partner required two batches of the candidate compound in different salt forms for formulation development. Since salt form can directly affect solubility, stability, bioavailability, scalability, and storage, the formulation process imposed strict parameters. Leveraging WuXi AppTec’s integrated platform, the peptide and formulation teams collaborated early in the process to ensure that the optimized synthetic product met downstream formulation needs—enabling seamless handoff and accelerating development timelines.
Through a series of efficient optimizations, the team successfully delivered two batches of the candidate compound with different salt forms within four months, exceeding the partner’s timeline by a full month.
This is just one example of how WuXi TIDES supports the development of complex peptide molecules. The team brings deep expertise in peptide synthesis, particularly for challenging scaffolds. For bicyclic and tricyclic peptides, WuXi TIDES applies a diverse set of cyclization strategies, including mono-, di-, and tri-thioether bridges, disulfide bridges, click cyclization, lactone and lactam formation, and olefin metathesis. The team also possesses specialized skills in N-alkylation, backbone modification, residue insertion, and non-standard linker synthesis—enabling comprehensive structure–activity relationship (SAR) exploration.
Accelerating Oral Cyclic Peptide Development through Cross-Functional Collaboration
In addition to its technical strengths in complex peptide manufacturing, WuXi TIDES demonstrated close cross-team collaboration in another case involving the discovery and development of an oral cyclic peptide therapy. This coordination proved essential in overcoming technical hurdles and reducing project timelines.
In 2023, a small biotech company identified a signaling pathway associated with weight loss. Inspired by its potential, the company set out to develop an oral peptide-based obesity therapy. However, lacking the internal capacity to produce large-scale peptide libraries, they turned to WuXi TIDES for support.
At the early discovery stage, the WuXi TIDES team generated a diverse peptide library consisting of over 1,700 cyclic peptide compounds, each with a purity exceeding 95%. By introducing varied side-chain mutations and applying multiple cyclization strategies, the team enabled broad chemical space exploration—helping the client rapidly identify high-potential drug candidates.
Beyond screening and candidate selection, one of the critical challenges in oral peptide development is production scale-up. Due to the inherently low bioavailability of oral peptides, required doses during animal studies can be dozens to hundreds of times greater than those for injectable formulations—placing additional demands on timely manufacturing.
While the client collaborated with the WuXi Biology team on pharmacokinetic (DMPK) and efficacy studies, WuXi TIDES' synthesis team closely coordinated with the WuXi Biology team to expedite data collection, feedback, and iterative optimization. Within just two weeks, they successfully produced multiple 50-gram batches of candidate peptides.
The partner expressed high satisfaction with both the collaboration and outcomes, commending WuXi TIDES for its scientific rigor and execution efficiency—both of which contributed to rapid project advancement. Based on this trust, the company opted to continue partnering with WuXi TIDES for subsequent development stages.
Transitioning a candidate from discovery to development is a pivotal milestone in the drug development process. At this stage, manufacturing must comply with increasingly stringent regulatory standards, including GLP and GMP. Switching manufacturing partners during this phase can lead to delays due to technology transfer. WuXi AppTec’s integrated CRDMO model eliminates this risk by offering end-to-end support under one platform.
In this case, the WuXi TIDES' CMC team proactively began development preparations while the candidate was still in the discovery stage. As a result, when the partner greenlit development-stage work, the synthesis process, analytical methods, and material transfer were completed in just one day—enabling an immediate transition into process optimization.
During optimization, the team rapidly evaluated eight synthesis conditions, increasing crude peptide purity by 15%. At the same time, improvements in purification raised recovery yields to over 90%. Within six weeks, the team successfully delivered the first 1-kilogram batch of GLP-grade peptide for preclinical studies.
In parallel, a second round of process optimization was launched to meet future scale-up requirements. Over the next six weeks, the team evaluated four manufacturing routes and successfully replaced a complex UAA building block with a more accessible, commercially available UAA. This substitution reduced procurement complexity, shortened lead times, and significantly lowered raw material costs. Further optimization of solid-phase synthesis techniques increased the crude peptide purity by over 30% and improved final yield by 50% compared with the initial 1-kilogram batch.
When the partner decided to initiate toxicology studies, they set an aggressive timeline for drug substance delivery. Thanks to proactive planning and strong cross-functional coordination across WuXi TIDES’ production, quality control, and logistics teams, detailed timelines were established even before candidate synthesis was complete.
The result: the team successfully delivered a second 6-kilogram batch of GLP-grade peptide within seven weeks—ensuring the partner could launch toxicology studies as scheduled. From lead optimization to GMP readiness, the project was completed in under 12 months.
Comprehensive Capabilities Empower the Future of Peptide Therapeutics
According to a recent review published in Signal Transduction and Targeted Therapy, nearly 40 peptide-based therapies had entered Phase 3 clinical development by the end of 2024. These late-stage candidates span diverse therapeutic areas, including diabetes, rare diseases, infectious diseases, ophthalmology, and oncology.
Peptide-drug conjugates (PDCs)—which involve coupling peptides with various functional payloads—are also emerging as a new growth frontier. Over 30 PDCs are now in clinical development, with payloads ranging from cytotoxic compounds (PDCs) and radiopharmaceuticals (RDCs) to advanced oligonucleotide drugs such as POCs and PPMOs.
WuXi TIDES has made early strategic investments in this rapidly evolving space, building a one-stop technology platform that integrates synthesis capabilities for oligonucleotides, peptides, monomers, ligands, linkers, and lipids. With deep experience in synthetic chemistry and broad coverage across diverse molecule types, the platform is designed to support a wide range of client needs—regardless of payload type, conjugation site, or molecular class—empowering partners to bring their drug development visions to life.
To support rising demand, WuXi TIDES continues to expand its peptide manufacturing capacity. By Q3 2025, total solid-phase synthesis reactor volume is expected to exceed 100,000 liters. Looking ahead, the team remains committed to helping partners fully unlock the therapeutic potential of peptides—bringing more innovative and high-quality medicines to patients around the world.
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来源：新浪财经
