編者按：高血脂是心血管疾病及相關(guān)死亡的重要風(fēng)險(xiǎn)因素。世界心臟聯(lián)盟（WHF）指出，全球約39%的成年人膽固醇水平升高，每年導(dǎo)致數(shù)百萬(wàn)人死亡。盡管他汀類藥物是常用的降脂藥物，但由于服藥依從性等問(wèn)題，許多患者仍難以達(dá)到目標(biāo)低密度脂蛋白膽固醇（LDL-C）水平。近年來(lái)，基于寡核苷酸的療法通過(guò)在肝臟靶向干預(yù)膽固醇的合成或代謝，正逐步改變高脂血癥的治療方式，有望實(shí)現(xiàn)每3至6個(gè)月注射一次，即可長(zhǎng)期穩(wěn)定降脂。其背后的關(guān)鍵推動(dòng)力之一，是基于N-乙酰半乳糖胺（GalNAc）的靶向遞送技術(shù)。目前，多款siRNA、反義寡核苷酸（ASO）以及堿基編輯療法均采用GalNAc偶聯(lián)技術(shù)進(jìn)行肝臟遞送，在臨床試驗(yàn)中展現(xiàn)出顯著且持久的降脂效果。為滿足全球合作伙伴的研發(fā)需求，藥明康德旗下獨(dú)特的CRDMO平臺(tái)WuXi TIDES，圍繞GalNAc分子及偶聯(lián)物建立了一體化服務(wù)平臺(tái)，覆蓋從藥物發(fā)現(xiàn)、CMC開(kāi)發(fā)，到商業(yè)化生產(chǎn)的全生命周期，加速將合作伙伴的創(chuàng)新構(gòu)想轉(zhuǎn)化為現(xiàn)實(shí)，造福全球病患。本文將從基于寡核苷酸的降脂療法出發(fā)，介紹GalNAc遞送技術(shù)以及WuXi TIDES團(tuán)隊(duì)如何助力合作伙伴應(yīng)對(duì)GalNAc偶聯(lián)藥物開(kāi)發(fā)中的挑戰(zhàn)。

從3個(gè)月一針到一次性治療，新一代療法正在改變高血脂治療模式

目前，多款針對(duì)膽固醇代謝靶點(diǎn)的siRNA和ASO療法正處于后期臨床開(kāi)發(fā)階段。它們通過(guò)在mRNA水平干預(yù)與膽固醇代謝相關(guān)蛋白的表達(dá)，僅需每3或6個(gè)月注射一次，便可顯著降低LDL-C水平。此類長(zhǎng)效療法不僅有望解決傳統(tǒng)療法中的依從性難題，還可靶向他汀類藥物難以干預(yù)的信號(hào)通路，為患者提供更全面的血脂管理手段。在減少給藥頻次的基礎(chǔ)上，更進(jìn)一步的堿基編輯療法正探索通過(guò)“一次性治療”實(shí)現(xiàn)長(zhǎng)期甚至永久的降脂效果，開(kāi)辟高脂血癥治療的新路徑。

▲部分處于臨床開(kāi)發(fā)階段的寡核苷酸和堿基編輯降脂療法（數(shù)據(jù)來(lái)源：公開(kāi)資料）

這些前沿療法的共同特征，是采用GalNAc偶聯(lián)技術(shù)以提升藥物在肝臟中的靶向遞送效率。有的將GalNAc直接偶聯(lián)至寡核苷酸片段本身，以提高穩(wěn)定性和細(xì)胞攝取效率；也有部分堿基編輯療法將GalNAc修飾在脂質(zhì)納米顆粒（LNP）表面，以增強(qiáng)遞送系統(tǒng)的組織特異性。

GalNAc偶聯(lián)技術(shù)：靶向肝臟的精準(zhǔn)遞送系統(tǒng)

GalNAc是半乳糖的氨基糖衍生物，可與肝細(xì)胞表面高度表達(dá)的去唾液酸糖蛋白受體（ASGPR）高親和力結(jié)合，促進(jìn)藥物的細(xì)胞內(nèi)吞。目前FDA已批準(zhǔn)7款siRNA療法，其中6款采用了GalNAc偶聯(lián)技術(shù)。這項(xiàng)技術(shù)同樣適用于ASO遞送，如2023年12月獲批的Wainua（eplontersen）即是成功應(yīng)用的代表。

▲GalNAc偶聯(lián)技術(shù)遞送寡核苷酸藥物的機(jī)制（圖片來(lái)源：參考資料[7]）

自問(wèn)世以來(lái)，GalNAc偶聯(lián)技術(shù)不斷迭代升級(jí)，無(wú)論是在化學(xué)修飾方式還是多價(jià)分子的設(shè)計(jì)合成方面，均取得顯著進(jìn)展。由于ASGPR對(duì)GalNAc的親和力與其配體數(shù)目密切相關(guān)，研究人員廣泛探索并開(kāi)發(fā)了多種三價(jià)、四價(jià)GalNAc簇（cluster）及其在寡核苷酸上的偶聯(lián)策略，以提高遞送效率。

▲多價(jià)GalNAc簇與寡核苷酸偶聯(lián)的不同方式（圖片來(lái)源：參考資料[3]）

隨著技術(shù)不斷成熟，GalNAc偶聯(lián)藥物的合成與工藝開(kāi)發(fā)日益復(fù)雜。WuXi TIDES團(tuán)隊(duì)在合成GalNAc分子方面擁有豐富經(jīng)驗(yàn)，已合成100多種GalNAc分子及其衍生物，包括單-GalNAc、三-GalNAc、四-GalNAc、GalNAc酰胺、GalNAc PFP酯、GalNAc N3和GalNAc-PEG偶聯(lián)物等。借助全面的平臺(tái)能力，WuXi TIDES能夠提供GalNAc定制合成、工藝開(kāi)發(fā)和生產(chǎn)一體化服務(wù)，支持從藥物發(fā)現(xiàn)到臨床開(kāi)發(fā)再到商業(yè)化生產(chǎn)。下面的案例將介紹WuXi TIDES如何幫助合作伙伴加速推進(jìn)GalNAc偶聯(lián)siRNA藥物的開(kāi)發(fā)。

14個(gè)月完成兩款GalNAc偶聯(lián)siRNA藥物IND申報(bào)準(zhǔn)備

一家生物技術(shù)公司在開(kāi)發(fā)用于治療心血管疾病的GalNAc偶聯(lián)siRNA候選藥物時(shí)，由于缺乏成熟的GalNAc分子來(lái)源，加上產(chǎn)率和粗純度低下等問(wèn)題，項(xiàng)目推進(jìn)受阻。他們找到了WuXi TIDES，尋求解決方案。

首先要解決的便是非常規(guī)GalNAc分子的供應(yīng)問(wèn)題。針對(duì)合作伙伴提出的特殊需求，團(tuán)隊(duì)迅速建立合成路線，采用先進(jìn)的流動(dòng)化學(xué)技術(shù)，并優(yōu)化了溶劑體系，使重結(jié)晶收率高達(dá)94.8%，4個(gè)月內(nèi)成功交付4.5公斤高純度定制GalNAc分子，有效保障了項(xiàng)目的原料供應(yīng)。

隨后，在關(guān)鍵的偶聯(lián)環(huán)節(jié)，憑借在多種偶聯(lián)類型、偶聯(lián)化學(xué)和修飾策略上的積累，WuXi TIDES團(tuán)隊(duì)選擇了具有高度選擇性的“點(diǎn)擊化學(xué)”策略，顯著降低副產(chǎn)物產(chǎn)生，簡(jiǎn)化合成和純化流程，使最終收率從13%提升至62%，粗品純度從18%提高到75%，確保了適合臨床試驗(yàn)的高純度和穩(wěn)定性。

同時(shí)，基于一體化CMC服務(wù)能力，WuXi TIDES團(tuán)隊(duì)平行開(kāi)展了分析方法、制劑開(kāi)發(fā)等多項(xiàng)工作，同時(shí)利用先進(jìn)的無(wú)菌灌裝生產(chǎn)線和優(yōu)化的生產(chǎn)流程設(shè)計(jì)，在GMP批次的生產(chǎn)中達(dá)到99%的產(chǎn)率，顯著降低了API的損失。多團(tuán)隊(duì)的全方位協(xié)作使兩款siRNA候選藥物在14個(gè)月內(nèi)順利完成了IND申報(bào)準(zhǔn)備，加速推進(jìn)至臨床階段。

以上案例只是WuXi TIDES一體化CRDMO平臺(tái)能力的一個(gè)縮影。除了GalNAc偶聯(lián)寡核苷酸，WuXi TIDES也可為GalNAc偶聯(lián)多肽藥物提供一站式開(kāi)發(fā)支持。隨著越來(lái)越多GalNAc偶聯(lián)藥物進(jìn)入臨床開(kāi)發(fā)階段，像這樣的產(chǎn)業(yè)協(xié)同將成為加快研發(fā)步伐的重要推動(dòng)力。

今年發(fā)表在

Nature Medicine

A Single Dose for Long-Lasting Cholesterol Reduction: How a Breakthrough Technology Is Reshaping Hyperlipidemia Management

Hyperlipidemia is a major contributor to cardiovascular disease and mortality. According to the World Heart Federation (WHF), about 39% of adults globally have elevated cholesterol levels, causing millions of deaths annually. While statins are commonly used to lower LDL-C, many patients fail to reach target levels due to poor adherence and other factors. Oligonucleotide-based therapies have recently emerged as a promising alternative, targeting cholesterol synthesis and metabolism directly in the liver.

These treatments offer long-lasting effects with dosing as infrequent as every three to six months—enabled largely by N-acetylgalactosamine (GalNAc)-based targeted delivery. Multiple approved and investigational siRNAs and antisense oligonucleotides (ASOs) now use GalNAc conjugation to enhance liver-specific delivery. Clinical trials have shown these therapies can achieve sustained lipid-lowering effects.

To meet rising demand in this field, WuXi TIDES, a unique CRDMO platform that is part of WuXi AppTec, has established an integrated service platform around GalNAc molecules and conjugates, covering from drug discovery and CMC development to commercial-scale manufacturing. This article introduces GalNAc delivery technologies from the perspective of oligonucleotide-based lipid-lowering therapies and illustrates how the WuXi TIDES team supports partners in overcoming the challenges of GalNAc-conjugated drug development.

New Generation of Therapies Is Reshaping Hyperlipidemia Management

Multiple siRNA and ASO therapies targeting cholesterol metabolism pathways are currently in late-stage clinical development. These candidates work by modulating mRNA expression of proteins involved in lipid regulation, achieving substantial LDL-C reductions with dosing required only once every three or six months.

These long-acting therapies not only address the issue of poor patient compliance but also target biological pathways that are difficult to modulate with statins, offering patients more comprehensive lipid control. This signals a potential paradigm shift in how hyperlipidemia is treated.

A unifying feature among these therapies is their reliance on GalNAc conjugation to facilitate targeted liver delivery. By conjugating GalNAc to oligonucleotide payloads, the therapies gain enhanced molecular stability and improved cellular uptake, ultimately increasing their therapeutic efficacy.

GalNAc Conjugation: A Precision Delivery Platform for Liver-Targeted Therapies

GalNAc, an amino sugar derivative of galactose, binds with high affinity to asialoglycoprotein receptors (ASGPRs), which are highly expressed on hepatocytes. This binding promotes efficient endocytosis of the GalNAc-conjugated therapeutic. Of the seven siRNA drugs approved by the U.S. FDA, six utilize GalNAc conjugation. The technology is also effective for ASO delivery, as demonstrated by the approval of Wainua (eplontersen) in December 2023.

Since its introduction, GalNAc conjugation has evolved significantly through advances in chemical modification and the development of multivalent GalNAc clusters. Research shows that ASGPR binding affinity improves with the number of GalNAc ligands present, prompting the development of tri- and tetra-valent GalNAc constructs and optimized strategies for their conjugation to oligonucleotides.

As the technology matures, the synthesis and process development of GalNAc-conjugated drugs have grown increasingly complex. WuXi TIDES brings extensive experience in this area, having synthesized more than 100 types of GalNAc molecules and derivatives—including mono-GalNAc, tri-GalNAc, tetra-GalNAc, GalNAc amidites, GalNAc PFP esters, GalNAc N3, and GalNAc-PEG conjugates. Through the Company’s comprehensive capabilities and capacity, WuXi TIDES offers GalNAc custom synthesis, process development, and manufacturing support from the discovery phase to commercial launch. The following case study illustrates how WuXi TIDES helped a biotech partner rapidly advance a GalNAc-siRNA candidate.

Fast-Track to Phase I: Two siRNA IND CMC Packages Completed in 14 Months

One biotech company developing a GalNAc-siRNA therapy for cardiovascular disease faced multiple challenges—including limited supply of a unique GalNAc molecule, low yield, and poor purity—which stalled their program. To overcome these hurdles, they partnered with WuXi TIDES.

The priority was to ensure a stable supply of the GalNAc molecule. WuXi TIDES quickly designed a customized synthetic route tailored to the client’s specifications. Using advanced flow chemistry and an optimized solvent system, the team achieved a 94.8% recrystallization yield. Within just four months, they successfully delivered 4.5 kilograms of high-purity, custom GalNAc—effectively securing the supply of the starting material for the GalNAc-siRNA conjugate and shortening development timelines.

Next came the critical conjugation step. Drawing on extensive expertise in conjugation chemistries and modification strategies, the WuXi TIDES team adopted a highly selective “Click Chemistry” approach, minimizing byproduct formation and simplifying synthesis and purification. As a result, the overall yield increased from 13% to 62%, and crude purity improved from 18% to 75%, ensuring the production of clinical-grade material with superior purity and stability.

In parallel, WuXi TIDES leveraged its integrated CMC capabilities to advance analytical method development and formulation optimization. Together with an advanced sterile fill-finish line and optimal process design, we achieved a batch yield of >99% in GMP production, significantly minimizing the overall loss of costly API. These coordinated efforts enabled two siRNA candidates to complete IND-enabling activities within just 14 months, accelerating progress toward the clinic.

The above case is just one example of the capabilities of WuXi TIDES’ integrated CRDMO platform. In addition to oligonucleotides, WuXi TIDES also provides comprehensive development solutions for GalNAc-conjugated peptide therapeutics. As more GalNAc-conjugated drugs advance into clinical development, integrated collaboration will be essential to accelerating innovation and bringing therapies to patients faster.

A recent article published in

Nature Medicine

參考資料：

[1] Fast-Track to Phase I: Two siRNA IND CMC Packages Completed in 14 Months. Retrieved July 9, 2025, from https://tides.wuxiapptec.com/wp-content/uploads/2024/07/Fast-Track-to-Phase-I-Two-siRNA-IND-CMC-Packages-Completed-in-14-Months-FINAL.pdf

[2] Zhang et al., (2025). Advancement of drugs conjugated with GalNAc in the targeted delivery to hepatocytes based on asialoglycoprotein receptor. Carbohydrate Research, https://doi.org/10.1016/j.carres.2025.109426

[3] Debacker et al., (2020). Delivery of Oligonucleotides to the Liver with GalNAc: From Research to Registered Therapeutic Drug. Molecular Therapy, https://doi.org/10.1016/j.ymthe.2020.06.015

[4] Kumar and Turnbull (2023). Targeted delivery of oligonucleotides using multivalent protein–carbohydrate interactions. Chem. Soc. Rev., DOI: 10.1039/D2CS00788F

[5] RNA gene therapies offer hope for millions with high cholesterol. Retrieved July 9, 2025, from https://www.nature.com/articles/d41591-025-00002-2

[6] Cholesterol. Retrieved July 10, 2025, from https://world-heart-federation.org/what-we-do/cholesterol/

[7] Cui et al., (2021). Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation. ACS Omega, DOI:10.1021/acsomega.1c01755.

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