▎藥明康德

編者按：多肽藥物已成為多種疾病的重要治療模式。今年發表的一篇綜述指出，近20年來，FDA批準的多肽藥物數目加速上升，顯示出這一領域蓬勃發展的趨勢。然而，多肽藥物開發仍面臨體內穩定性不足和細胞滲透性差等挑戰，需通過多種工程化改造手段提升其成藥性。藥明康德旗下WuXi TIDES圍繞多肽藥物搭建了一體化CRDMO平臺，提供多種類型的多肽，包括線性、環狀和?度修飾的多肽，以及非天然氨基酸、連接?、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。本文將通過一款口服多肽療法的發現和開發故事，展示這一平臺如何助力合作伙伴高效應對多肽藥物研發中的多重挑戰。

圖片來源：參考資料[2]

從上千個多肽化合物到一款候選藥物，賦能口服多肽發現

隨著GLP-1藥物在肥胖癥治療中展現出顯著療效，減重療法的研發成為產業焦點之一。盡管基于GLP-1信號通路的療法仍占據主流，一些新銳公司已開始探索非GLP-1類減重機制。其中，一家生物技術公司發現了一條全新的非GLP-1通路，在肥胖或超重人群中具有潛在的減重效果。

該公司希望圍繞這一機制開發一款口服多肽減重療法。然而，口服多肽藥物的開發面臨諸多挑戰：天然多肽由氨基酸組成，容易被酶降解，且難以通過胃腸道粘膜高效吸收。因此，為了改善其穩定性和生物利用度，候選多肽需要經過環化、側鏈修飾、非天然氨基酸（UAA）替換等多種工程化改造。作為一家僅有20余名員工的臨床階段生物技術公司，該客戶缺乏構建和篩選大規模多肽化合物庫的能力，難以支持其研發策略的順利實施，因此找到了WuXi TIDES團隊。

圖片來源：123RF

在藥物發現早期階段，首要目標是篩選出與靶點結合效果最佳的配體。根據客戶需求，WuXi TIDES項目團隊生產出總計包括超過1700種不同結構環肽的多肽化合物庫，所有化合物純度均超過95%。在合成過程中，團隊在環肽中引入多樣化側鏈突變，并運用點擊環化與烯烴復分解環化（RCM）等多種環化策略生成環肽結構，廣泛探索化學空間，助力客戶快速識別出潛力候選化合物。

通過初步篩選，10個化合物顯示出強效且高度選擇性的生物活性。團隊迅速完成這些化合物的放大合成，用于驗證和進行詳細的藥理學特征分析。值得注意的是，由于口服多肽的生物利用度有限，動物實驗階段的用量與注射型多肽相比要高出數十甚至上百倍，對化合物的及時生產提出更高要求。

WuXi TIDES的發現化學團隊與藥明康德測試團隊緊密協作，持續優化分子結構，推進3個在體外和體內檢測中表現良好的先導化合物。僅用一年時間，便基于效力、穩定性和可開發性等多重指標，幫助客戶確定了一個臨床前候選化合物。為配合客戶持續推進的測試節奏，WuXi TIDES團隊連續成功交付了8個批次（每批約50克）的該候選化合物，單批交付周期僅為2至3周，顯著加快了項目進度。

客戶對WuXi TIDES在多肽合成方面的專業能力與高效執行給予高度認可，也因此在藥物發現階段結束后，決定繼續攜手推進后續藥物開發工作。

無縫連接開發階段，工藝優化加速大規模口服多肽生產

從藥物發現階段向開發階段過渡，是新藥研發的關鍵轉折點。進入開發階段后，藥物的生產流程需遵守更嚴格的監管要求，如GLP和GMP等標準。若在此階段更換生產廠商，技術交接過程可能導致項目延誤。得益于WuXi TIDES一體化CRDMO服務平臺的協同能力，在這一項目中，負責CMC業務的多肽工藝研發團隊提前布局，在候選化合物仍處于發現階段時即啟動前期準備工作。因此，當客戶決定啟動開發階段工作時，僅用1天時間就完成了合成工藝與分析方法的轉移及物料準備，實現了兩階段之間的無縫銜接，迅速進入了工藝優化環節。

進入開發階段后，工藝研發團隊快速評估了4條合成路線，并篩選了8組反應條件，大幅提升了工藝的可放大性和穩定性，最終，粗品純度和最終產率相對發現階段分別提高了70%和140%以上。

在候選化合物生產尚未完成之際，WuXi TIDES團隊便與負責生產、質量控制（QC）和物流管理的各團隊制定了詳盡的時間表，以確保后續工作迅速且有序進行。最終，項目團隊在6個月內成功將工藝從50克示范批次放大至1公斤示范批次，并完成6公斤GLP級別候選藥物的交付，充分保障了客戶能夠按計劃啟動由WuXi Biology團隊支持的初步毒理學研究。

目前，客戶的主打候選藥物正在推進原料藥（API）工藝開發工作，為啟動IND支持性研究鋪平道路。該公司對本次合作給予高度評價，特別強調WuXi TIDES的科學實力、執行效率和交付速度是其管線得以快速推進的關鍵因素。

本案例只是WuXi TIDES一體化CRDMO平臺能力的一個縮影。目前WuXi TIDES擁有分布在10個研發和生產基地的1400余名科學家，提供化合物合成、新型單體、連接子和配體、寡核苷酸、多肽及復雜化學偶聯物的工藝開發與任何規模的生產服務。除了化學合成，還提供各類注射劑型與灌裝形式的制劑開發、生產、包裝、貼標和配送服務。展望未來，團隊將繼續助力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療法和高質量藥物。

CRDMO: An Integrated Platform Accelerates the Development of Innovative Oral Peptide Therapeutics

Peptide-based drugs have become an important therapeutic modality for a wide range 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. However, peptide drug development still faces challenges such as poor in vivo stability and limited cellular permeability. Overcoming these obstacles requires extensive chemical engineering to improve efficacy. WuXi TIDES, an integral part of WuXi AppTec, has built an integrated CRDMO platform focused on peptides. The platform offers high-throughput library synthesis and custom peptide synthesis, supporting a wide range of peptides, including linear, cyclic, and highly modified peptides, unnatural amino acids (UAAs), linkers, toxins and peptide conjugates. WuXi TIDES simplifies peptide drug development by providing discovery, CMC development, and the entire manufacturing supply chain under one roof. This article presents a case study on the discovery and development of an oral peptide therapy, highlighting how the platform helps partners efficiently address the complex challenges of peptide R&D.

From Thousands of Peptides to a Lead Candidate

The rise of GLP-1 receptor agonists as breakthrough treatments for diabetes and obesity has sparked a wave of innovation across the industry. When a clinical-stage biotech company with a bold vision set out to develop a differentiated, orally available peptide drug targeting a non-GLP-1 pathway for weight control, they turned to WuXi TIDES.

While cyclic peptides offer enhanced pharmacological properties – such as improved stability and bioavailability – their synthesis can be challenging, depending on the complexity of the cyclization process. During the library synthesis stage, the WuXi TIDES Discovery Chemistry team supported the client’s search through diverse side-chain mutations and various cyclization types, including ring-closing metathesis (RCM) and Nobel Prize-winning “Click Chemistry”[1] (a set of efficient selective chemical reactions ideal for drug development). They successfully delivered multiple rounds of different libraries totaling more than 1,700 cyclic peptides with greater than 95% purity, each at a scale of 1–5 mg.

From the initial screen, 10 hits exhibited strong and selective activity. These hits were rapidly resynthesized and scaled for validation and detailed pharmacological profiling. WuXi TIDES’ Discovery Chemistry team worked closely with the Testing team to refine molecular properties, advancing three optimized leads with favorable in vitro and in vivo profiles. Within one year, a preclinical candidate was selected based on its potency, stability, and developability. WuXi TIDES’ Discovery Chemistry team successfully delivered eight consecutive ~50 g scale batches of this candidate with an expedited lead time of 2-3 weeks per batch to support the client’s evolving testing needs as it moved forward. Impressed by the speed and scientific rigor of the program, the client chose to continue with WuXi TIDES into the development phase.

Seamless Transition to Development: Optimizing Processes for Scalable Oral Peptide Manufacturing

The transition from discovery to development marks a critical milestone in drug R&D. Once a program enters development, production processes must meet more stringent regulatory requirements, such as GLP and GMP standards. Changing manufacturers at this stage can involve delays, revalidation, and fragmented coordination that slow progress and increase risk. However, due to our fully integrated CRDMO platform, the tech and material transfer from the Discovery Chemistry team to our API Development and Analytical teams was conducted seamlessly, taking just one business day – eliminating bottlenecks and accelerating timelines.

To meet the client’s urgent delivery requirements, all teams from WuXi TIDES worked closely together. The Development team managed to scale up from a 50 g demo batch to a 1 kg demo batch and a 6 kg GLP batch within six months to support the client’s preliminary toxicological study. The peptide development team scouted four routes and screened eight sets of conditions to greatly enhance the scalability and robustness of the process, increasing the crude purity and final yield by more than 70% and 140%, respectively. Even before the final synthesis process was completed, the WuXi TIDES team had already coordinated with manufacturing, quality control (QC), and logistics teams to establish a detailed timeline—ensuring downstream activities could proceed efficiently.

Today, the client’s lead candidate is advancing through API process development, paving the way for IND-enabling studies. The client expressed strong satisfaction with the collaboration – highlighting our scientific excellence, operational efficiency, and speed as key to the success of their pipeline advancement.

This project is one of many examples demonstrating WuXi TIDES’ integrated CRDMO capabilities. With more than 1,400 scientists across 10 global R&D and manufacturing sites, WuXi TIDES provides comprehensive services for discovery synthesis, process development and manufacturing of novel monomer, linker, and ligand development, as well as oligonucleotides, peptides, and complex conjugates at any scale. In addition to chemical synthesis, WuXi TIDES also offers formulation development, manufacturing, packaging, labeling, and distribution services for oral and injectable dosage forms and filling formats.

Looking ahead, WuXi TIDES remains committed to empowering global partners to unlock the full potential of peptide therapeutics—bringing more innovative therapies and high-quality medicines to patients worldwide. At WuXi TIDES, we move fast so our clients can move forward.

參考資料：

[1] The Nobel Prize in Chemistry 2022. Retrieved June 24, 2025, from https://www.nobelprize.org/prizes/chemistry/2022/popular-information/

[2] Xiao et al., (2025). Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines. Signal Transduction and Targeted Therapy, https://doi.org/10.1038/s41392-024-02107-5

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