小分子、多肽、寡核苷酸齊上陣，新一代偶聯技術正在重寫精準醫學的邊界

編者按：隨著精準醫學的不斷發展，如何將治療性藥物高效且特異性地遞送至病灶組織，已成為新藥研發的重要課題。通過將能與目標組織中特異蛋白或受體結合的配體與治療性載荷進行偶聯，科研人員已在臨床實踐中探索出一類兼具安全性與療效的策略。在常見的單克隆抗體之外，小分子、多肽、寡核苷酸等分子也可作為靶向配體，實現藥物的精準遞送。然而，這類偶聯策略在提升靶向性的同時，也伴隨著復雜的化學合成挑戰。藥明康德在化學業務上的豐富經驗為開發這類新一代療法打下堅實的基礎。旗下WuXi TIDES全面的平臺能力可為復雜的偶聯藥物提供一體化解決方案。本文將聚焦偶聯藥物增強藥物組織特異性遞送的多種模式，并介紹WuXi TIDES如何通過一體化CRDMO平臺，助力合作伙伴加速偶聯藥物的開發進程。

偶聯藥物的核心結構包括三部分：用于識別靶點的配體、具有治療活性的有效載荷，以及連接兩者的連接子。配體可特異性識別并結合靶細胞表面高表達的受體，進而觸發受體介導的內吞作用，將藥物高效遞送至細胞內部。與傳統的被動靶向或全身暴露相比，偶聯策略能夠在分子層面“導航”藥物，在提高療效的同時顯著降低毒性。

目前，全球已有近20款抗體偶聯藥物（ADC）獲批上市。值得一提的是，除了傳統的ADC，近年來采用小分子、多肽或寡核苷酸作為靶向配體的新一代偶聯藥物也在快速發展，其所搭載的有效載荷涵蓋傳統細胞毒性化合物、放射性同位素以及寡核苷酸等創新治療手段，呈現出多樣化趨勢。

圖片來源：123RF

例如，N-乙酰半乳糖胺（GalNAc）是一種天然糖類結構，能夠特異性結合肝細胞表面豐富表達的去唾液酸糖蛋白受體（ASGPR），被廣泛應用于肝臟疾病治療藥物的遞送。在siRNA和反義寡核苷酸（ASO）藥物中，GalNAc偶聯策略在遞送效率和組織靶向性方面表現尤為突出。已有多款GalNAc偶聯寡核苷酸藥物獲得FDA批準，它們不僅支持皮下注射、患者依從性好，還能高效富集于肝細胞，降低所需劑量，同時具有良好的安全性。

多肽也是一類重要的靶向配體。相比抗體，多肽具有分子量小、組織穿透能力強、易于化學合成等優勢，成為新一代偶聯藥物研發的關鍵方向之一。通過靶向腫瘤組織中過表達的整合素、生長抑素受體（SSTR）或促性腺激素釋放激素受體（LHRH）等靶點，多肽偶聯藥物可實現精準打擊腫瘤細胞。

例如，諾華（Novartis）開發的Lutathera（177Lu-dotatate）是一款多肽偶聯放射性藥物，通過靶向SSTR遞送核素，用于治療神經內分泌腫瘤。在研發管線中，ITM Isotope Technologies的177Lu-edotreotide在胃腸胰神經內分泌腫瘤的3期臨床試驗中，近日已遞交新藥申請（NDA）。此外，Bicycle Therapeutics公司致力于雙環肽療法，其多款靶向nectin-4和EphA2等靶點的雙環肽偶聯藥物已進入臨床階段，用于遞送細胞毒性或放射性藥物，精準殺傷腫瘤細胞。

在寡核苷酸藥物遞送方面，多肽同樣展現出廣闊前景。Bicycle公司已與Ionis Pharmaceuticals達成合作，聯合開發靶向轉鐵蛋白受體的雙環肽，用于將ASO藥物遞送至肌肉及中樞神經系統，提升療效與組織特異性。

▲不同偶聯藥物類型（圖片來源：參考資料[4]）

除了小分子和多肽，適配體也是一種有潛力的靶向配體。適配體由單鏈DNA或RNA構成，具備三維結構，能以高親和力和特異性與靶點結合，被譽為“化學抗體”。目前已有兩款適配體藥物獲得FDA批準，用于治療年齡相關性黃斑變性。由于其分子量小、結構可控、免疫原性低等特點，適配體非常適合用于偶聯藥物的構建。多個適配體偶聯抗癌藥物正在臨床開發中，旨在提升細胞毒性藥物的腫瘤特異性遞送效率，并進一步探索其在寡核苷酸或納米結構精準遞送方面的應用潛力。

藥明康德旗下WuXi TIDES搭建了獨特的CRDMO平臺，為全球合作伙伴開發寡核苷酸、多肽藥物及相關化學偶聯物（TIDES藥物）提供高效、靈活和高質量解決方案。在多肽偶聯藥物開發方面，其全面的多肽平臺結合了小分子化學能力，支持多肽-毒素、多肽-金屬、多肽-GalNAc、多肽-寡核苷酸和放射性核素偶聯藥物等偶聯藥物的開發。WuXi TIDES的一體化平臺讓多個團隊能夠并行攻關，密切合作，顯著提高項目推進速度。下面的這個案例將展示這一平臺如何助力合作伙伴，加速一款環肽-GalNAc偶聯藥物的研發進程。

一體化平臺賦能多肽偶聯藥物開發

在該案例中，合作伙伴的目標是將一款處于發現階段的環肽-GalNAc偶聯藥物推進至IND申請。然而，這一過程面臨多重挑戰：由于藥物分子結構復雜，并且合成過程中一個關鍵多肽中間產物溶解度很低，導致整體產率偏低。同時，合作伙伴以產品的最終商業化為核心目標，這也意味著在早期開發中，如何開發具有成本效益的生產工藝成為首要任務之一。

針對這些挑戰，WuXi TIDES的原料藥和制劑與分析團隊緊密協作，開展聯合攻關。首先要解決的是總產率偏低的問題。研發團隊利用WuXi TIDES內部的GalNAc合成能力，采取了一系列質量控制措施，成功解決了GalNAc原料中的關鍵性雜質問題。團隊通過添加合適的配體等舉措，為提高關鍵多肽中間產物的溶解度奠定了堅實基礎。通過對合成步驟的多重優化，團隊將總產率從發現階段的10%提高至20%，提升幅度高達100%。憑借多個團隊的高效協作，WuXi TIDES僅用12個月便順利將該藥物推進至IND申報階段。客戶對產率的顯著提升非常滿意，并決定繼續與WuXi TIDES團隊進行GMP生產合作。

在確保順利推進的同時，WuXi TIDES團隊還致力于降低藥物生產成本。他們對環肽-GalNAc偶聯藥物的生產和純化流程進行了系統性優化。通過替換昂貴的原材料，使原材料成本降低8%；將關鍵中間產物的生產步驟由8步縮減為7步，使整體生產成本再降低10%；并利用多柱逆流溶劑梯度純化（MCSGP）技術，在縮短生產周期的同時進一步降低了成本。最終，憑借這一系列持續優化措施，與早期的1公斤GLP批次相比，生產8公斤GMP批次時，每公斤的成本降低了71%。

圖片來源：123RF

WuXi TIDES同樣可以為復雜的寡核苷酸偶聯藥物提供一站式解決方案，支持從藥物發現到CMC開發再到商業化?產。平臺能力支持寡核苷酸與GalNAc、多肽、適配體、脂質、藥物和其它定制小分子的偶聯。

通過兼顧“精準靶向”與“有效治療”，偶聯藥物為新藥研發帶來了全新思路。豐富的配體與載荷選擇不僅提升了組織特異性，還拓展了藥物類型與適應癥的邊界。未來，WuXi TIDES將繼續依托其一體化、端到端的CRDMO平臺，支持合作伙伴推進包括多肽偶聯藥物、寡核苷酸偶聯藥物在內的多類偶聯藥物研發，助力前沿科技轉化為惠及全球患者的突破性療法。

CRDMO: New Conjugates Are Expanding the Boundaries of Precision Medicine

As precision medicine continues to advance, the ability to efficiently and specifically deliver therapeutic agents to diseased tissues has become a critical focus in drug development. One promising strategy involves conjugating therapeutic payloads with ligands that can bind to specific proteins or receptors expressed in target tissues. This approach has demonstrated both safety and efficacy in clinical practice. In addition to monoclonal antibodies, small molecules, peptides, and oligonucleotides have also emerged as targeting ligands, enabling precise drug delivery. However, these conjugation strategies often come with significant synthetic complexity. WuXi AppTec’s deep expertise in chemistry has laid a strong foundation for the development of such next-generation therapies. Through its comprehensive WuXi TIDES platform, WuXi AppTec provides integrated solutions for complex conjugates. This article explores various conjugation strategies that enhance tissue-specific drug delivery and highlights how WuXi TIDES accelerates conjugates development through its integrated CRDMO platform.

A typical conjugated drug consists of three core components: a targeting ligand, a therapeutic payload, and a linker that connects the two. The ligand is designed to selectively bind to receptors that are highly expressed on the surface of target cells, triggering receptor-mediated endocytosis and enabling efficient intracellular drug delivery. Compared to passive targeting or systemic exposure, this strategy allows drugs to be guided at the molecular level, improving efficacy while minimizing toxicity. To date, nearly 20 ADCs have been approved globally. Importantly, a new generation of conjugated drugs is emerging. They utilize small molecules, peptides, or oligonucleotides as targeting ligands, and feature a diverse range of payloads, including traditional cytotoxic agents, radioactive isotopes, and oligonucleotides, signaling a broadening of therapeutic modalities.

Among these innovations, N-acetylgalactosamine (GalNAc) has become a widely used ligand for liver-targeted drug delivery. This naturally occurring sugar binds specifically to the asialoglycoprotein receptor (ASGPR), which is abundantly expressed on hepatocytes. The GalNAc conjugation strategy has shown particularly strong performance in siRNA and antisense oligonucleotide (ASO) therapies, with several GalNAc-conjugated oligonucleotide drugs now approved by the FDA. These agents offer the convenience of subcutaneous administration, excellent patient compliance, efficient hepatic accumulation, lower required doses, and favorable safety profiles.

Peptides also serve as highly effective targeting ligands. Compared to antibodies, peptides offer smaller molecular size, better tissue penetration, and ease of chemical synthesis, making them an important focus for next-generation conjugated drug development. By targeting receptors that are overexpressed in tumors, such as integrins, somatostatin receptors (SSTR), or luteinizing hormone-releasing hormone (LHRH) receptors, peptide-drug conjugates can selectively eliminate cancer cells. For example, Lutathera (177Lu-dotatate), developed by Novartis, is a peptide-radionuclide conjugate that targets SSTR for the treatment of neuroendocrine tumors. In the pipeline, ITM Isotope Technologies’ 177Lu-edotreotide has achieved its primary endpoint in a Phase 3 clinical trial for gastroenteropancreatic neuroendocrine tumors. The company recently filed a New Drug Application (NDA). Additionally, Bicycle Therapeutics is advancing multiple clinical-stage programs involving bicyclic peptide conjugates that target antigens such as nectin-4 and EphA2, delivering cytotoxic or radiotherapeutic payloads to precisely kill tumor cells.

Peptides are also showing promise in the delivery of oligonucleotide-based therapies. Bicycle Therapeutics, in collaboration with Ionis Pharmaceuticals, is developing bicyclic peptides targeting the transferrin receptor to deliver ASO drugs to muscle and central nervous system tissues. This approach aims to enhance both therapeutic efficacy and tissue specificity.

In addition to small molecules and peptides, aptamers represent another class of promising targeting ligands. These single-stranded DNA or RNA molecules form three-dimensional structures that bind to target molecules with high affinity and specificity, earning them the moniker “chemical antibodies.” Two aptamer-based drugs have already been approved by the FDA for the treatment of age-related macular degeneration. With their small molecular size, structural controllability, and low immunogenicity, aptamers are ideally suited for the design of next-generation conjugated therapies. Multiple aptamer-drug conjugates are currently in clinical development to improve the tumor-specific delivery of cytotoxic agents. Researchers are also exploring aptamer-based systems for the targeted delivery of oligonucleotides and nanoscale structures.

WuXi TIDES, a specialized CRDMO platform under WuXi AppTec, provides efficient, flexible, and high-quality solutions for the development of oligonucleotides, peptides, and related chemically conjugated molecules—collectively known as "TIDES" drugs. The platform integrates advanced peptide capabilities with small molecule chemistry, supporting various peptide conjugates, including but not limited to: peptide-toxin, peptide-metal, peptide-GalNAc, peptide-PMO, peptide-oligonucleotide, radionuclide drug conjugate (RDC), etc. The platform’s integrated nature enables cross-functional teams to collaborate in parallel, significantly accelerating project timelines. The following case study illustrates how WuXi TIDES’ integrated platform enables partners to accelerate the development of a peptide-GalNAc conjugate therapy.

Integrated Platform Empowering Peptide Conjugate Development

In this project, the partner’s goal was to advance a peptide-GalNAc conjugate drug candidate, still at the discovery stage, toward an IND submission. The program, however, faced several challenges. The molecular structure of the candidate was highly complex, and a critical peptide intermediate in the synthesis process exhibited very poor solubility, leading to low overall yield. At the same time, because the partner prioritized eventual commercialization, establishing a cost-effective manufacturing process became a central objective in early development.

To address these obstacles, WuXi TIDES’ API, Drug Product and Analytical teams worked in close collaboration. The most urgent issue was the low overall yield. By leveraging WuXi TIDES’ in-house GalNAc synthesis capabilities, the R&D team implemented a series of quality control measures that resolved critical impurity issues in the GalNAc raw material. The team improved the poor solubility of a key peptide intermediate by directly using fractions and adding ligands. Through multiple rounds of process optimization, they not only enhanced the solubility of the key peptide intermediate but also doubled the overall yield, from 10% at the discovery stage to 20%. Thanks to efficient cross-team collaboration, WuXi TIDES advanced the program to the IND submission stage within just 12 months. The client, highly satisfied with the improved yield, chose to continue working with the WuXi TIDES team on GMP manufacturing.

In parallel with improving yield, the WuXi TIDES team also focused on reducing manufacturing costs. They conducted systematic optimization of the production and purification processes for the peptide-GalNAc conjugate. Replacing costly raw materials reduced material costs by 8%. Streamlining the production steps of a key intermediate from eight steps to seven further lowered overall costs by 10%. In addition, adopting multi-column counter-current solvent gradient purification (MCSGP) technology not only shortened the production cycle but also reduced costs further. Ultimately, this series of continuous optimizations enabled the team to reduce the cost per kilogram by 71% for an 8 kg GMP batch compared to the earlier 1 kg GLP batch.

WuXi TIDES also offers one-stop solutions for complex oligonucleotide-drug conjugates, supporting projects from discovery and development through to commercial-scale manufacturing. The platform enables the conjugation of oligonucleotides with GalNAc, peptides, aptamers, lipids, therapeutic agents, and other custom small molecules.

By uniting “precise targeting” with “effective therapy,” conjugated drugs offer a new paradigm in drug innovation. The ability to select from a wide variety of ligands and payloads not only enhances tissue specificity but also expands the scope of drug types and indications. Looking ahead, WuXi TIDES will continue to leverage its fully integrated, end-to-end CRDMO platform to support partners in advancing diverse classes of conjugated drugs—including peptide- and oligonucleotide-based conjugates—ultimately helping to transform scientific breakthroughs into life-changing therapies for patients worldwide.

參考資料：

[1] Yan et al., (2024). Different Targeting Ligands-Mediated Drug Delivery Systems for Tumor Therapy. Pharmaceutics, doi: 10.3390/pharmaceutics16020248

[2] Fu et al., (2023). Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope? Acta Pharmaceutica Sinica B, https://doi.org/10.1016/j.apsb.2022.07.020

[3] Peptide Conjugate Discovery. Retrieved July 30, 2025, from https://tides.wuxiapptec.com/services-solutions/peptide/discovery/peptide-conjugate/

[4] Guo et al., (2024). Advances in peptide-based drug delivery systems. Heliyon, https://doi.org/10.1016/j.heliyon.2024.e26009

[5] Oligonucleotide Conjugate Discovery. Retrieved August 1, 2025, from https://tides.wuxiapptec.com/services-solutions/oligonucleotide/discovery/oligo-conjugate/

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