8個月，從PCC到遞交IND：藥明康德一體化平臺如何攻克寡核苷酸脂質偶聯(lián)藥物開發(fā)難題 | Bilingual

寡核苷酸是近年來發(fā)展迅速的一類新興分子類型。隨著技術演進，肝外遞送正成為新的研發(fā)趨勢，有望將這類療法的應用拓展至更廣泛的疾病領域。脂質偶聯(lián)作為實現(xiàn)肝外遞送的關鍵技術路徑之一，在從實驗室走向臨床的過程中仍面臨諸多挑戰(zhàn)。

一家生物技術公司曾就其管線中的一款寡核苷酸脂質偶聯(lián)（siRNA-lipid conjugate）藥物，與藥明康德建立合作。彼時，該候選藥物正處于從臨床前候選化合物（PCC）階段向新藥臨床試驗申請（IND）階段推進的準備過程中。

這類藥物本身的復雜性，已經讓這項工作充滿挑戰(zhàn)。而客戶提出的一個特殊要求則進一步加大了項目的難度——在不到九個月的緊急時間內，完成公斤級siRNA脂質偶聯(lián)藥物的工藝放大及生產并提交IND。

這一時間要求遠超行業(yè)常規(guī)節(jié)奏。通常，一個典型的siRNA脂質偶聯(lián)藥物從PCC到完成IND申請準備的各項CMC工作，大約需要11個月。這意味著，項目核心開發(fā)階段的時間需大幅壓縮。

面對這一極具挑戰(zhàn)的目標，藥明康德旗下WuXi TIDES以靈活的策略以及高效的執(zhí)行力，在8個月內便完成了從臨床前候選化合物到臨床試驗申請所需的整套CMC資料，項目順利通過客戶驗收。

圖片來源：123RF

豐富的化學經驗，為客戶解決關鍵工藝挑戰(zhàn)

故事，要從寡核苷酸藥物的遞送說起。

過去十年，寡核苷酸藥物的臨床成功高度集中于肝臟適應癥。以GalNAc偶聯(lián)為代表的肝臟遞送技術，憑借其對肝細胞的高效靶向，極大地推動了siRNA與反義寡核苷酸（ASO）藥物的快速發(fā)展。然而，當治療靶點拓展至肌肉、心臟或中樞神經系統(tǒng)（CNS）等肝外組織時，遞送難度顯著增加。以CNS為例，血腦屏障、組織特異性屏障以及靶細胞受體分布的差異性，共同構成了核酸藥物“肝外遞送”領域亟待突破的核心挑戰(zhàn)。

在這一背景下，寡核苷酸脂質偶聯(lián)藥物應運而生。通過選用具有不同化學結構的脂質分子與寡核苷酸偶聯(lián)，可調控其在血液中的蛋白結合特性，從而實現(xiàn)肝外組織的靶向遞送。因此，這類偶聯(lián)物被視為實現(xiàn)肝外遞送的重要工具之一。

然而，這一新型遞送工具的開發(fā)并非坦途。脂質自身水溶性較低，使得這類偶聯(lián)物在化學設計、合成純化、分析表征、制劑開發(fā)等環(huán)節(jié)均面臨相應的技術挑戰(zhàn)。同時，其開發(fā)涉及小分子、寡核苷酸、偶聯(lián)化學等多領域的技術能力，要求研發(fā)團隊具備深厚的技術深度，同時平臺擁有較高的全鏈條整合能力。此外，核酸藥物在雜質控制與遺傳毒性評估等方面面臨更嚴格的監(jiān)管，對質量管控提出更高要求。

面對上述挑戰(zhàn)，藥明康德通過一體化、端到端的CRDMO平臺，助力全球客戶加速這類新型寡核苷酸偶聯(lián)藥物的開發(fā)。

多年來，藥明康德在化學領域持續(xù)深耕，為解決偶聯(lián)化學的復雜性奠定了堅實基礎。在寡核苷酸浪潮興起初期，公司就開始進行能力布局，逐步搭建起專注于寡核苷酸、多肽及相關化學偶聯(lián)藥物的WuXi TIDES平臺。通過建立全面的能力，該平臺能夠為復雜的寡核苷酸偶聯(lián)藥物提供一體化解決方案。

針對寡核苷酸脂質偶聯(lián)藥物這一細分領域，團隊同樣在技術興起之初便積極投入，通過持續(xù)的項目經驗積累，已形成了成熟的技術體系和復雜問題解決能力。

公開數據顯示，僅在2025年，WuXi TIDES就合成并交付了超過7000個寡核苷酸脂質偶聯(lián)化合物。這背后是團隊對多種偶聯(lián)位點（如寡核苷酸鏈的3′端和5′端）以及各類修飾（包括核苷酸的堿基、糖骨架和磷骨架）的全面掌握。針對siRNA、雙靶點siRNA、ASO等不同類型的脂質偶聯(lián)，平臺已開發(fā)出超過20種可供偶聯(lián)的脂質類型。

在工藝開發(fā)層面，WuXi TIDES平臺對酰胺偶聯(lián)、酰胺縮合、點擊化學、氧化磷酰胺化等多種偶聯(lián)技術均積累了豐富的實操經驗。此外，公司的原料藥及制劑基地空間距離近，且遵守統(tǒng)一的質量體系，也為高質量、快速交付項目奠定了重要基礎。

故事回到前述的客戶項目中。正是這些從大量實踐中沉淀下來的技術、能力和經驗，讓WuXi TIDES團隊能夠快速響應客戶需求。

面對緊迫的時間窗口和復雜的技術要求，團隊決定不再沿用原本的寡核苷酸固相合成策略——那條路可以說是障礙重重。原工藝策略中，先將脂質固定在固相載體（樹脂）上，然后在其上進行寡核苷酸固相合成。然而，定制化脂質載體的交付周期往往長達兩到三個月，項目還沒開始合成，就卡在了供應瓶頸上。而脂質本身的疏水性和空間位置，又讓反應效率大打折扣，粗品純度低、收率也不理想。更麻煩的是，與脂質相關的雜質或殘留物（如游離脂質、脂質降解產物、脂質siRNA的聚集體等）使下游純化和內毒素控制更加棘手，很可能在IND階段引發(fā)監(jiān)管風險。

時間、合成效率、質量——多重壓力集中在同一個項目上。

為克服上述挑戰(zhàn)，團隊重新設計了整條路線。他們放棄了原來的方案，轉而采用一種新策略：先完成寡核苷酸固相合成，后進行液相脂質偶聯(lián)。這一調整立刻釋放了項目的靈活性——脂質由內部同步合成，與寡核苷酸的生產并行推進。僅此一舉，開發(fā)周期就縮短了約兩個月。由于脂質不再依賴外部采購，質量和供應穩(wěn)定性也更加可控。

新的偶聯(lián)工藝帶來了高達95%的轉化率，粗品純度提升了約20%。下游也同步簡化，原本需要兩步的純化被縮減成一步。團隊還成功開發(fā)并實施了有效的內毒素控制策略，覆蓋原料、設備、純化流程等方面，最終使API中的內毒素水平穩(wěn)定控制在0.05 EU/mg以下，遠低于監(jiān)管要求。

一體化CRDMO平臺助力項目開發(fā)“加速度”

如果說技術能力和經驗決定了這個項目“能做多好”，那么一體化平臺則決定了“能做多快”。

完成工藝重構后，WuXi TIDES團隊以一體化模式推進項目——脂質合成、工藝開發(fā)、分析方法驗證，以及制劑開發(fā)，所有環(huán)節(jié)都在同一平臺下并行推進，無縫銜接。

具體而言，在原料藥團隊完成Demo批次后，工藝優(yōu)化立即開啟，處方前研究及制劑開發(fā)、原料藥GLP批次生產也在同步推進中。制劑工程批次生產緊隨其后，原料藥GMP批次很快并行推進，為臨床供應做好準備。分析方法開發(fā)與驗證則貫穿整個周期。

這種協(xié)同并非簡單的“同時工作”。它建立在團隊對上下游各環(huán)節(jié)技術邏輯的深度理解之上——大家都清楚上游將交付什么、下游需要什么，從而壓縮等待時間和溝通成本，更建立在一體化平臺體系下，工藝、分析方法、質量體系的一致性，從工藝放大到分析方法轉移，都大大提高了成功率，減少在方法轉移時出現(xiàn)的偏差和重復驗證工作，使數據完整性更好，有助于CMC資料的一致性與監(jiān)管接受度。由專職項目管理人員負責整個項目的協(xié)調，進一步提升了執(zhí)行效率與風險控制。

簡而言之，跨階段、跨團隊、跨基地所產生的摩擦及風險大幅降低，讓項目更快、更穩(wěn)地往前推進。這背后，是一體化平臺將技術能力與協(xié)同機制真正融合在一起的力量，也是它區(qū)別于傳統(tǒng)碎片化協(xié)作的核心價值所在。

從肝臟靶向到肝外組織遞送，寡核苷酸脂質偶聯(lián)藥物展現(xiàn)出廣闊的前景。盡管研發(fā)之路充滿挑戰(zhàn)，但正是這些挑戰(zhàn)，才更能彰顯創(chuàng)新技術和療法造福患者的真正價值。在本案例中，藥明康德將階段性研發(fā)周期從11個月縮短到8個月——這不僅是效率的提升，更是公司持續(xù)踐行“讓天下沒有難做的藥，難治的病”這一愿景的生動縮影。

Conquering Oligonucleotide-Lipid Conjugate Process Challenges: How WuXi AppTec Accelerates Client Timelines

Oligonucleotides represent a rapidly emerging modality. As the technology evolves, extrahepatic delivery is becoming a new trend, with the potential to expand oligonucleotide-based therapies into a broader range of disease areas.Lipid conjugation, as one of the key approaches for achieving extrahepatic delivery, still presents considerable challenges during the transition from laboratory to clinical development.

A biotechnology company collaborated with WuXi AppTec to advance an oligonucleotide-lipid conjugate drug candidate. At that time, the candidate (siRNA-lipid conjugate) was preparing to advance from the preclinical candidate compound (PCC) stage toward investigational new drug (IND) application.

The intrinsic complexity of this class of therapeutics had already made the program highly challenging. A specific client requirement further increased the level of difficulty: completing kilogram-scale manufacturing of a siRNA-lipid conjugate and achieving IND submission within an accelerated timeline of fewer than 9 months.

This timeline was significantly faster than the industry norm. Under typical circumstances, an oligonucleotide-lipid conjugate program generally requires approximately 11 months to progress from PCC to IND-enabling CMC readiness. In this case, the core development timeline had to be substantially compressed.

Faced with this highly demanding objective, the integrated WuXi TIDES team adopted a flexible development strategy combined with rapid execution, ultimately delivering the program at high quality.Within 8 months, the team completed the full set of CMC activities required to advance the program from preclinical candidate to IND submission, and the project successfully passed client acceptance.

Image source: 123RF

Chemistry Expertise Solves Critical Process Challenges for Clients

The story begins with oligonucleotide drug delivery.

Over the past decade, the clinical success of oligonucleotide drugs has been largely limited to liver-related indications. Liver-directed delivery technologies, such as GalNAc conjugation, have enabled efficient targeting of hepatocytes, driving the rapid development of siRNA and antisense oligonucleotide (ASO) therapies.

However, when therapeutic targets shift to extrahepatic tissues — such as muscle, heart, and the central nervous system (CNS) — additional challenges arise. The blood-brain barrier in the CNS, tissue-specific barriers, and differences in target cell receptor distribution have made extrahepatic delivery one of the major challenges in the field of nucleic acid therapeutics.

In this context, oligonucleotide-lipid conjugates have been explored as a potential solution.By conjugating oligonucleotides with lipid molecules of different chemical structures, it may be possible to modulate protein binding properties in the blood and thereby direct drug distribution to extrahepatic tissues.These conjugates are therefore considered as a promising tool for achieving extrahepatic delivery.

Nevertheless, the development of such conjugates is technically challenging. Due to the poor water solubility of lipids, these molecules present hurdles in chemical design, synthesis and purification, analytical characterization, and formulation development. Furthermore, developing oligonucleotide-lipid conjugates requires expertise across small molecules, oligonucleotides, and conjugation chemistry, placing high demands on both technical depth and end-to-end integration capabilities. In addition, oligonucleotide drugs face tighter regulatory scrutiny for impurity control and genotoxicity assessment, imposing higher demands on quality control.

In response to these challenges, WuXi AppTec's integrated CRDMO platform supports clients in accelerating the development of such novel conjugates.

Over the years, WuXi AppTec has continuously built extensive chemistry expertise, laying a solid foundation for tackling the complexities of conjugation chemistry. Early in the rise of oligonucleotides, WuXi AppTec began building the WuXi TIDES platform, which focuses on oligonucleotides, peptides, and related chemical conjugation drugs, with established capabilities to provide end-to-end solutions for complex oligonucleotide conjugates.

For oligonucleotide-lipid conjugates, the team made early strategic investments as the technology emerged. Through ongoing project work, the team has established a comprehensive technical framework and accumulated extensive experience in addressing complex development and manufacturing challenges.

In 2025 alone, the platform delivered over 7,000 oligonucleotide-lipid conjugates.This figure reflects the team's experience with various conjugation sites on the 3′ and 5′ ends of strands, base or sugar skeleton of nucleotide, and phosphorus backbone.For lipid conjugates of various modalities, including siRNA, dual-targeting siRNA, and ASO, the platform has developed more than 20 lipid moieties suitable for conjugation.

At the process development level, the platform has accumulated extensive hands-on experience with various conjugation technologies, including amide coupling, amide condensation, click chemistry, and oxidative phosphoramidation. The close proximity of drug substance and drug product sites, together with a unified quality system, provides a strong foundation for high-quality, rapid project delivery.

The story returns to the client program described earlier. It was precisely this accumulation of technical expertise, platform capability, and hands-on experience that enabled the WuXi TIDES team to respond rapidly to the client’s needs.

Faced with an aggressive timeline and complex technical requirements, the team decided not to continue with the original solid-phase oligonucleotide synthesis strategy — a route that had become increasingly constrained. Under the initial process design, the customized lipid-functionalized support typically required a procurement lead time of two to three months, creating a supply bottleneck before synthesis could even begin. At the same time, the poor solubility and steric hindrance of the lipid significantly reduced coupling efficiency, resulting in low crude purity and unsatisfactory yield. Lipid-associated materials (such as free lipids, lipid degradation products, aggregates of siRNA-lipid complexes, etc.) also complicated downstream purification and endotoxin control, potentially introducing regulatory risk at the IND stage.

Timeline pressure, synthetic efficiency, and manufacturing quality all converged within a single program.

To overcome these challenges, the team redesigned the entire process route. Instead of following the original strategy, they adopted a new approach: completing oligonucleotide synthesis first, followed by solution-phase lipid conjugation. This change immediately improved operational flexibility. Lipid building blocks were synthesized in-house in parallel with oligonucleotide production, shortening the overall development timeline by approximately 2 months. By eliminating dependence on external lipid supply, the team also gained greater control over quality and supply reliability.

The new conjugation process achieved up to 95% homogeneous conversion, increased the crude purity by approximately 20%.Downstream processing was streamlined as well, with two purification steps consolidated into one. The team also developed and implemented a dedicated endotoxin control strategy across raw materials, equipment, and purification workflow,ultimately maintaining endotoxin levels in the final API below 0.05 EU/mg — well within regulatory expectations.

The Integrated CRDMO Platform Supports Acceleration of Project Development

If technical expertise and execution determined how well the project could be delivered, the integrated platform determined how quickly it could move forward.

Following the process redesign, the WuXi TIDES team advanced the program under an integrated development model.Lipid synthesis, process development, analytical method validation, and formulation development were all executed in parallel on a unified platform, enabling seamless coordination across functions.

Specifically, once the API team delivered the demo batch, process optimization began immediately, with pre-formulation/formulation development and API GLP production running in parallel. Drug product engineering batches followed, and API GMP batches were quickly advanced alongside to prepare clinical supply. Analytical method development and validation continued throughout the entire cycle.

This synergy is more than “working in parallel.” It rests on a deep, shared understanding of technical dependencies across upstream and downstream activities: each team knows what the prior stage will deliver and what the next stage needs, which cuts wait time and reduces communication inefficiencies. Built on an integrated platform with consistent processes, analytical methods, and quality systems, this approach increases success rates, minimizes deviations and repetitive re-validation during method transfers, and strengthens data integrity—supporting CMC consistency and regulatory acceptance. One dedicated project manager coordinates program end-to-end, further improving execution efficiency and risk control.

In short, cross-stage, cross-team, and cross-site frictions and risks are substantially reduced, enabling faster, more reliable project progression. This seamless integration of technical capability and collaborative mechanisms is the platform’s core value and differentiator versus traditional fragmented models.

Oligonucleotide-lipid conjugates offer a promising route from liver-targeted to extrahepatic delivery, though development remains technically challenging. In this case, reducing the R&D timeline from 11 to 8 months reflects not only improved efficiency but also the value of integrated capabilities in addressing complex development hurdles. This is consistent with WuXi AppTec’s vision: every drug can be made, and every disease can be treated.

參考資料：

[1] Chaudhari (2026). Evolution of the psoriasis therapy landscape. Nature Reviews Drug Discovery, Doi: https://doi.org/10.1038/d41573-026-00097-3

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