同行致遠 | 精準抗癌的新模式！一體化平臺助力多肽藥物開發(fā) | Bilingual

編者按：近年來，多肽療法作為抗癌領域的新興治療模式，憑借高特異性和低免疫原性等優(yōu)勢，正為患者帶來更多治療選擇。多肽藥物不僅能直接干預腫瘤相關信號通路，還可作為藥物遞送系統(tǒng)的關鍵載體，實現(xiàn)靶向遞送，在癌癥診斷和治療中展現(xiàn)出廣闊前景。然而，這類療法在研發(fā)過程中面臨合成難度高、修飾類型多等挑戰(zhàn)，對化學合成、分析表征及規(guī)模化生產(chǎn)提出更高要求。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(huán)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(lián)物的合成服務，支持從藥物發(fā)現(xiàn)、CMC開發(fā)到商業(yè)化生產(chǎn)的各個階段。本文將聚焦多肽療法在癌癥治療中的應用潛力，并介紹WuXi TIDES如何助力合作伙伴高效應對研發(fā)挑戰(zhàn)、加速實現(xiàn)臨床轉化。

多肽藥物在癌癥診療中的應用

自1989年以來，已經(jīng)有近30款多肽藥物獲得美國FDA批準用于癌癥的治療和診斷，涵蓋促性腺激素釋放激素（GnRH）類似物、生長抑素類似物（SSA）、前列腺膜抗原（PSMA）靶向多肽、抗體偶聯(lián)藥物（ADC）、多肽偶聯(lián)藥物（PDC）以及多肽受體放射性療法（PRRT）等類別。

多肽可通過多種機制發(fā)揮抗癌作用：作為受體激動劑或拮抗劑調(diào)節(jié)信號通路；抑制腫瘤生存所必需的關鍵酶；與放射性化合物偶聯(lián)，用于診斷成像或靶向放射治療。多肽還可以作為毒性載荷、連接子或者靶向載體，成為ADC或PDC的重要組成部分。其多功能性、高特異性和低毒性，使多肽成為現(xiàn)代癌癥治療的重要工具。

▲基于多肽的抗癌藥物發(fā)展歷史（圖片來源：參考資料[5]）

此外，基于多肽的疫苗正成為腫瘤治療的一種變革性策略，其優(yōu)勢在于免疫原性明確、安全性良好和模塊化設計。這類疫苗將腫瘤相關抗原，尤其是新抗原，遞送至樹突狀細胞（DCs）等抗原呈遞細胞（APCs），從而刺激細胞毒性T淋巴細胞（CTL）介導的腫瘤清除。與佐劑聯(lián)合使用，可增強APC的成熟和表位呈遞，進一步增強適應性免疫反應。

▲多肽癌癥疫苗的作用機制（圖片來源：參考資料[6]）

盡管前景可期，多肽藥物在臨床應用中仍面臨諸多挑戰(zhàn)，包括穩(wěn)定性低、膜滲透性差，體內(nèi)清除速度快、口服生物利用度有限等。因此需要對多肽骨架的化學修飾以及環(huán)化等策略來提升藥物特征。同時，與傳統(tǒng)小分子藥物相比，多肽藥物更為復雜，需要滿足諸如非天然氨基酸合成、肽庫合成、偶聯(lián)化合物合成、放大生產(chǎn)工藝研發(fā)以及多肽制劑開發(fā)等方面的多種需求。因此，臨床階段的生物技術公司往往需要與專業(yè)賦能平臺合作，這也正是本文中案例公司選擇WuXi TIDES的原因。

以精準的解決方案完成復雜雙環(huán)肽放大生產(chǎn)

該公司的一款在研藥物是一款帶有偶聯(lián)糖基側鏈的雙環(huán)肽，起始合成路線需要先分別合成雙環(huán)肽和側鏈，然后再將兩者進行化學偶聯(lián)。然而，雙環(huán)肽原始合成路線中部分步驟產(chǎn)生的中間產(chǎn)物溶解性很低，不僅大幅度降低了總產(chǎn)率，更使后續(xù)反應難以順利進行，為放大生產(chǎn)帶來了極大挑戰(zhàn)。此外，為提高最終產(chǎn)物的純度和產(chǎn)率，在雙環(huán)肽與側鏈偶聯(lián)之前需增加額外的純化步驟。整個生產(chǎn)流程對團隊的固相和液相合成能力，以及產(chǎn)物的分離和純化能力都提出了極高要求。

針對這些挑戰(zhàn)，WuXi TIDES團隊制定了針對性的解決方案。通過優(yōu)化合成路線并調(diào)整反應溶劑，顯著提高了中間產(chǎn)物的溶解性，為后續(xù)放大生產(chǎn)奠定了基礎。同時，負責分離和純化的團隊根據(jù)該雙環(huán)肽設計了量身定制的純化方案。團隊在短短6周內(nèi)完成了放大生產(chǎn)的工藝優(yōu)化，并通過一次15克的小型合成實驗驗證了新工藝的可行性。

在這個項目中，合作伙伴要求生產(chǎn)兩批具有不同鹽型的候選化合物用于藥物制劑的開發(fā)。藥物的鹽型直接影響溶解度、穩(wěn)定性、生物利用度、放大生產(chǎn)以及儲存等多個方面，因此制劑開發(fā)過程對鹽型參數(shù)提出了嚴格要求。依托藥明康德一體化賦能平臺的優(yōu)勢，早在工藝優(yōu)化過程中，公司的多肽研發(fā)與制劑團隊就進行了緊密溝通與協(xié)作，確保工藝優(yōu)化后合成的產(chǎn)品滿足制劑開發(fā)團隊的需求，這樣的無縫銜接進一步縮短了項目開發(fā)時間。

在最終產(chǎn)物的純化階段，團隊進一步優(yōu)化純化工藝，不僅提高了每次處理粗樣品的能力，還將單次純化時間壓縮到不到60分鐘。經(jīng)過一系列高效的工藝優(yōu)化，團隊在4個月內(nèi)順利完成了兩批分別為400克和500克的不同鹽型候選化合物的生產(chǎn)，比合作伙伴的預期提前了整整一個月。

上面僅是WuXi TIDES多肽平臺助力復雜多肽開發(fā)的一個典型案例。團隊擁有豐富的復雜肽合成經(jīng)驗，在環(huán)化策略上，可采用多種策略合成雙環(huán)肽和三環(huán)肽，包括單/雙/三硫醚鍵環(huán)化、硫硫鍵環(huán)化、點擊環(huán)化、內(nèi)酯環(huán)化、內(nèi)酰胺環(huán)化和烯烴復分解環(huán)化等；在合成能力上，具備N-烷基取代、骨架修飾、殘基插入和非標準連接子合成等專業(yè)能力，有效支持多肽藥物的結構活性探索。

在多肽偶聯(lián)藥物領域，WuXi TIDES配備有包括多肽、單體、配體、連接子、脂質(zhì)等在內(nèi)的“一站式”技術平臺，擁有豐富的化學合成經(jīng)驗，可以滿足來自不同客戶、不同分子類型、不同偶聯(lián)位置、不同載荷的差異化需求，全面助力合作伙伴更好地實現(xiàn)新藥研發(fā)夢想。

近年來，WuXi TIDES也在持續(xù)推進多肽產(chǎn)能建設，預計2025年多肽固相合成反應釜總體積將持續(xù)提升。展望未來，團隊將繼續(xù)助力合作伙伴充分發(fā)揮多肽療法的巨大潛力，為患者帶來更多創(chuàng)新療法和高質(zhì)量藥物。

CRDMO: A New Precision Anticancer Paradigm – Integrated Platform Accelerates Peptide Drug Development

In recent years, peptide therapeutics have emerged as a promising and innovative treatment model in oncology. With advantages such as high specificity and low immunogenicity, they offer patients more therapeutic options. These drugs can directly interfere with tumor-related signaling pathways and also act as key carriers in drug delivery systems to achieve targeted delivery—showing strong potential in both cancer diagnosis and treatment.

However, their development is not without challenges. Peptide therapeutics are often characterized by high synthetic complexity, diverse modification requirements, and stringent quality demands. This places considerable pressure on chemical synthesis, analytical characterization, and large-scale manufacturing. Addressing these needs, WuXi TIDES, part of WuXi AppTec, has built an integrated CRDMO platform dedicated to peptide therapeutics. The platform provides synthesis services for linear, cyclic, and highly modified peptides, as well as non-natural amino acids, linkers, toxins, and peptide conjugates, supporting all stages from drug discovery and CMC development to commercial manufacturing. This article explores the potential of peptide therapeutics in cancer treatment and highlights how WuXi TIDES enables partners to overcome development challenges and accelerate clinical translation.

Applications of Peptide Drugs in Cancer Diagnosis and Treatment

Since 1989, nearly 30 peptide drugs have been approved by the U.S. FDA for cancer treatment and diagnosis. These span multiple categories, including gonadotropin-releasing hormone (GnRH) analogues, somatostatin analogues (SSA), prostate-specific membrane antigen (PSMA)-targeting peptides, antibody-drug conjugates (ADCs), peptide-drug conjugates (PDCs), and peptide receptor radionuclide therapies (PRRT).

Peptides can fight cancer through a variety of mechanisms: acting as receptor agonists or antagonists to modulate signaling pathways; inhibiting key enzymes essential for tumor survival; or conjugating with radionuclides for diagnostic imaging and targeted radiotherapy. They can also serve as toxic payloads, linkers, or targeting moieties, forming essential components of ADCs or PDCs. Thanks to their multifunctionality, high specificity, and low toxicity, peptides have become a cornerstone in modern cancer therapy.

In addition to therapeutic peptides, peptide-based vaccines have gained attention as a transformative strategy in oncology. These vaccines offer well-defined immunogenicity, favorable safety profiles, and a modular design. They work by delivering tumor-associated antigens—particularly neoantigens—to antigen-presenting cells (APCs) such as dendritic cells (DCs), stimulating cytotoxic T lymphocyte (CTL)-mediated tumor eradication. When co-administered with adjuvants, these vaccines can enhance APC maturation and epitope presentation, thereby amplifying adaptive immune responses.

Despite their promise, peptide drugs face several clinical challenges, including low stability, poor membrane permeability, rapid clearance, and limited oral bioavailability. Overcoming these obstacles often requires chemical modifications to the peptide backbone, cyclization strategies, and advanced formulation approaches.

Compared to traditional small molecules, peptide therapeutics are more complex to develop, demanding specialized capabilities such as non-natural amino acid synthesis, peptide library generation, conjugate synthesis, scale-up process development, and formulation optimization. This complexity means that biotech companies in the clinical stage frequently seek partnerships with specialized enabling platforms—that is why the company featured in this case study selected 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.

The above case demonstrates how multi-team collaboration within the WuXi TIDES integrated CRDMO platform can shorten development timelines at critical stages and resolve technical challenges. This model is equally applicable to the development of peptide-conjugated drugs.

WuXi TIDES has made early strategic investments in the PDC 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. 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.

參考資料：

[1] Vadevoo et al., (2023). Peptides as multifunctional players in cancer therapy. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-023-01016-x

[2] Bauso et al., (2024). Biological Activity of Natural and Synthetic Peptides as Anticancer Agents. Int J Mol Sci, doi: 10.3390/ijms25137264

[3] Nsereko et al., (2025). Innovative Peptide Therapeutics in the Pipeline: Transforming Cancer Detection and Treatment. . Int J Mol Sci, doi: 10.3390/ijms26146815

[4] Case Study: Accelerating Next-Generation Oral Cyclic Peptide from Lead Optimization to GMP Readiness. Retrieved August 12, 2025, from https://tides.wuxiapptec.com/resources/case-study-accelerating-next-generation-oral-cyclic-peptide-from-lead-optimization-to-gmp-readiness/

[5] Musaimi (2024). Peptide Therapeutics: Unveiling the Potential against Cancer—A Journey through 1989. Cancers, https://doi.org/10.3390/cancers16051032

[6] Zheng et al., (2025). Therapeutic Peptides: Recent Advances in Discovery, Synthesis, and Clinical Translation. Int J Mol Sci, https://doi.org/10.3390/ijms26115131

免責聲明：本文僅作信息交流之目的，文中觀點不代表藥明康德立場，亦不代表藥明康德支持或反對文中觀點。本文也不是治療方案推薦。如需獲得治療方案指導，請前往正規(guī)醫(yī)院就診。

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