編者按：在新一代精準(zhǔn)治療浪潮中，偶聯(lián)藥物憑借獨(dú)特的分子設(shè)計(jì)理念，正成為精準(zhǔn)治療的重要模式。作為一種新興的治療模式，偶聯(lián)藥物通過(guò)將高選擇性的靶向載體與高效藥物載荷結(jié)合，實(shí)現(xiàn)了“精準(zhǔn)遞送、靶向釋放”的目標(biāo)。近年來(lái)，隨著靶向載體的選擇、偶聯(lián)技術(shù)及有效載荷類型的不斷豐富，偶聯(lián)藥物在癌癥、感染、自身免疫及代謝疾病等多個(gè)領(lǐng)域展現(xiàn)出廣闊的應(yīng)用前景。本文將聚焦偶聯(lián)藥物中的連接子和藥物載荷部分的結(jié)構(gòu)和功能，并展示藥明康德旗下WuXi TIDES一體化平臺(tái)如何助力合作伙伴加速偶聯(lián)藥物開(kāi)發(fā)。

偶聯(lián)藥物的設(shè)計(jì)理念基于“精準(zhǔn)遞送”的治療思路。它通常包括三個(gè)核心部分：識(shí)別靶點(diǎn)的靶向分子、連接子（linker）以及藥物載荷（payload）。三者協(xié)同作用，實(shí)現(xiàn)疾病部位的高效識(shí)別、穩(wěn)定運(yùn)輸與載荷的選擇性釋放，從而顯著提升治療指數(shù)，并降低全身毒性。目前，全球已有多款使用單克隆抗體和多肽作為靶向分子的偶聯(lián)藥物獲批上市，近年來(lái)，基于小分子或寡核苷酸作為靶向配體的新一代偶聯(lián)藥物也在快速發(fā)展。靶向分子之外，連接子和載荷的設(shè)計(jì)近年來(lái)也呈現(xiàn)出多樣化趨勢(shì)。

▲不同偶聯(lián)藥物類型（圖片來(lái)源：參考資料[4]）

連接子：控制載荷釋放與穩(wěn)定性的“分子橋梁”

連接子是靶向載體與載荷之間的“橋梁”，在藥物的體內(nèi)穩(wěn)定性和活性釋放中起到?jīng)Q定性作用。理想的連接子應(yīng)在血液循環(huán)中保持穩(wěn)定，而在特定條件（如pH變化、特定蛋白酶或還原環(huán)境）下被精準(zhǔn)切斷，從而釋放活性藥物。

連接子主要分為可裂解型和不可裂解型兩大類?？闪呀庑瓦B接子又可依據(jù)裂解條件細(xì)分為酸可裂解型、酶可裂解型和還原可裂解型等多種類型。

▲不同類型的連接子（圖片來(lái)源：參考資料[2]）

不可裂解型連接子在血液循環(huán)中的穩(wěn)定性高，脫靶效應(yīng)較低。藥物釋放需要依靠細(xì)胞將偶聯(lián)藥物內(nèi)吞到細(xì)胞內(nèi)部，依賴細(xì)胞內(nèi)蛋白質(zhì)降解過(guò)程。然而，這種連接子構(gòu)建的偶聯(lián)藥物可能在連接子斷裂之前，藥物的其他結(jié)構(gòu)先發(fā)生裂解，從而產(chǎn)生非預(yù)期代謝物。

酸可裂解型連接子主要有腙和碳酸酯這兩種結(jié)構(gòu)，它們?cè)谒嵝阅[瘤微環(huán)境或細(xì)胞內(nèi)體、溶酶體中被裂解，而在中性的血液循環(huán)中保持相對(duì)穩(wěn)定。這種類型的連接子可以促進(jìn)載荷在酸性腫瘤微環(huán)境中的釋放，但是它們?cè)谘獫{中的穩(wěn)定性不高，可能導(dǎo)致載荷過(guò)早釋放而產(chǎn)生毒副作用。

腫瘤微環(huán)境中的谷胱甘肽（GSH）水平是正常細(xì)胞的4倍，這有利于調(diào)控由可還原的二硫鍵連接的載荷在腫瘤微環(huán)境中的可控釋放。

酶可裂解型連接子可被腫瘤微環(huán)境或溶酶體中高度表達(dá)的特定酶選擇性降解，例如基質(zhì)金屬蛋白酶（MMP）和組織蛋白酶B。有些蛋白酶在細(xì)胞外或血液循環(huán)中沒(méi)有活性，這意味著基于這類連接子的偶聯(lián)藥物在血液循環(huán)中能夠保持穩(wěn)定。

連接子的優(yōu)化設(shè)計(jì)直接影響偶聯(lián)藥物的體內(nèi)半衰期、靶向選擇性及藥效持續(xù)時(shí)間，是平衡療效與安全性的關(guān)鍵環(huán)節(jié)。選擇連接子時(shí)需要考慮因素包括：連接子是否易于與靶向配體和載荷進(jìn)行連接，并且不影響配體對(duì)其受體的親和力；連接子的性質(zhì)對(duì)偶聯(lián)的載荷本身理化屬性的影響；以及與有效載荷的偶聯(lián)位點(diǎn)能否保證載荷的有效和特異性釋放等等。

藥物載荷：決定療效的“戰(zhàn)斗單元”

藥物載荷是偶聯(lián)的核心功能單元，通常為具有高效細(xì)胞毒性或生物活性的分子，用于在靶點(diǎn)處發(fā)揮治療作用。根據(jù)治療目的不同，偶聯(lián)藥物可搭載多種類型的載荷，其中包括：

細(xì)胞毒性藥物：包括紫杉醇衍生物、拓?fù)洚悩?gòu)酶抑制劑，微管抑制劑等藥物類型，主要用于治療癌癥。

放射性同位素：可通過(guò)與靶向配體偶聯(lián)，形成具有治療作用的靶向藥物或者用于癌癥診斷的成像試劑。例如，Ga-68 DOTATOC由放射性同位素鎵-68和生長(zhǎng)抑素類似物DOTATOC偶聯(lián)生成，已經(jīng)獲得FDA的批準(zhǔn)作為正電子發(fā)射計(jì)算機(jī)斷層掃描（PET）的放射性顯影劑，用于神經(jīng)內(nèi)分泌腫瘤的診斷。諾華（Novartis）開(kāi)發(fā)的放射性配體療法Lutathera（Lu-177 dotatate）已經(jīng)獲得FDA批準(zhǔn)用于治療生長(zhǎng)抑素受體陽(yáng)性的胃腸胰神經(jīng)內(nèi)分泌腫瘤（GEP-NET）患者。該公司的另一款放射性配體療法Pluvicto（Lu-177 vipivotide tetraxetan）也已獲批治療去勢(shì)抵抗性前列腺癌患者。

此外，偶聯(lián)的載荷還可以包括靶向特定信號(hào)通路的小分子抑制劑或調(diào)節(jié)劑，以及包括寡核苷酸和多肽在內(nèi)的創(chuàng)新生物活性分子。這些不同類型的載荷拓展了偶聯(lián)藥物在癌癥治療、抗感染、以及診療一體化方面的應(yīng)用潛力。

通過(guò)合理匹配載荷類型與釋放機(jī)制，偶聯(lián)藥物可實(shí)現(xiàn)在靶點(diǎn)組織的高效積聚與精準(zhǔn)殺傷，為多種難治性疾病提供了新的治療思路。然而，這類療法復(fù)雜的化學(xué)合成過(guò)程為開(kāi)發(fā)帶來(lái)了重大挑戰(zhàn)。

藥明康德在化學(xué)業(yè)務(wù)上的豐富經(jīng)驗(yàn)為開(kāi)發(fā)這類新一代療法打下堅(jiān)實(shí)的基礎(chǔ)。藥明康德旗下WuXi TIDES搭建了獨(dú)特的CRDMO平臺(tái)，為全球合作伙伴開(kāi)發(fā)寡核苷酸、多肽藥物及相關(guān)化學(xué)偶聯(lián)物（TIDES藥物）提供高效、靈活和高質(zhì)量解決方案。在多肽偶聯(lián)藥物開(kāi)發(fā)方面，其全面的多肽平臺(tái)結(jié)合了小分子化學(xué)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(lián)藥物等偶聯(lián)藥物的開(kāi)發(fā)。WuXi TIDES的一體化平臺(tái)讓多個(gè)團(tuán)隊(duì)能夠并行攻關(guān)，密切合作，顯著提高項(xiàng)目推進(jìn)速度。下面的這個(gè)案例將展示這一平臺(tái)如何助力合作伙伴，加速一款環(huán)肽-GalNAc偶聯(lián)藥物的研發(fā)進(jìn)程。

一體化平臺(tái)賦能多肽偶聯(lián)藥物開(kāi)發(fā)

在該案例中，合作伙伴的目標(biāo)是將一款處于發(fā)現(xiàn)階段的GalNAc偶聯(lián)環(huán)肽藥物推進(jìn)至IND申請(qǐng)。然而，這一過(guò)程面臨多重挑戰(zhàn)：由于藥物分子結(jié)構(gòu)復(fù)雜，并且合成過(guò)程中一個(gè)關(guān)鍵多肽中間產(chǎn)物溶解度很低，導(dǎo)致整體產(chǎn)率偏低。同時(shí)，合作伙伴以產(chǎn)品的最終商業(yè)化為核心目標(biāo)，這也意味著在早期開(kāi)發(fā)中，如何建立具有成本效益的生產(chǎn)流程成為首要任務(wù)之一。

針對(duì)這些挑戰(zhàn)，WuXi TIDES的原料藥（API）和制劑研發(fā)與分析團(tuán)隊(duì)緊密協(xié)作，開(kāi)展聯(lián)合攻關(guān)。首先要解決的是總產(chǎn)率偏低的問(wèn)題。研發(fā)團(tuán)隊(duì)利用WuXi TIDES內(nèi)部的GalNAc合成能力，采取了一系列質(zhì)量控制措施，成功解決了GalNAc原料中的關(guān)鍵性雜質(zhì)問(wèn)題。團(tuán)隊(duì)自行生產(chǎn)的高純度多肽和GalNAc原料，為提高關(guān)鍵多肽中間產(chǎn)物的溶解度奠定了堅(jiān)實(shí)基礎(chǔ)。通過(guò)對(duì)合成步驟的多重優(yōu)化，不僅改善了關(guān)鍵多肽中間產(chǎn)物的溶解度，還將總產(chǎn)率從發(fā)現(xiàn)階段的10%提高至20%，提升幅度為100%。憑借多個(gè)團(tuán)隊(duì)的高效協(xié)作，WuXi TIDES僅用12個(gè)月便順利將該藥物推進(jìn)至IND申報(bào)階段?？蛻魧?duì)產(chǎn)率的顯著提升非常滿意，并決定繼續(xù)與WuXi TIDES團(tuán)隊(duì)進(jìn)行GMP生產(chǎn)合作。

在確保順利推進(jìn)的同時(shí)，WuXi TIDES團(tuán)隊(duì)還致力于降低藥物生產(chǎn)成本。他們對(duì)GalNAc偶聯(lián)環(huán)肽的生產(chǎn)和純化流程進(jìn)行了系統(tǒng)性優(yōu)化。通過(guò)替換昂貴的原材料，使原材料成本降低8%；將關(guān)鍵中間產(chǎn)物的生產(chǎn)步驟由8步縮減為7步，使整體生產(chǎn)成本再降低10%；并利用多柱逆流溶劑梯度純化（MCSGP）技術(shù)，在縮短生產(chǎn)周期的同時(shí)進(jìn)一步降低了成本。最終，憑借這一系列持續(xù)優(yōu)化措施，團(tuán)隊(duì)在生產(chǎn)8公斤GMP藥物批次時(shí)，與生產(chǎn)1公斤GLP藥物批次時(shí)相比，實(shí)現(xiàn)了成本降低71%。

通過(guò)兼顧“精準(zhǔn)靶向”與“有效治療”，偶聯(lián)藥物為新藥研發(fā)帶來(lái)了全新思路。豐富的配體、連接子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(yīng)癥的邊界。未來(lái)，WuXi TIDES將繼續(xù)依托其一體化、端到端的CRDMO平臺(tái)，支持合作伙伴推進(jìn)偶聯(lián)藥物的研發(fā)，助力前沿科技轉(zhuǎn)化為惠及全球患者的突破性療法。

From Linkers to Payloads: The Technology Innovations Driving the New Era of Drug Conjugates

Amid the new wave of precision therapeutics, drug conjugates are emerging as a key modality, driven by their unique molecular design principles. As an innovative therapeutic approach, conjugates combine highly selective targeting moieties with potent payloads to achieve precise delivery and targeted release. In recent years, with the expansion of targeting moiety options, advances in conjugation technologies, and diversification of payload types, conjugates have demonstrated broad application potential across oncology, infectious diseases, autoimmune disorders, and metabolic diseases. This article focuses on the structure and function of linkers and payloads in conjugates, and illustrates how WuXi TIDES, an integrated platform under WuXi AppTec, is empowering partners to accelerate the development of conjugated therapies.

At the heart of the drug conjugate design lies the principle of precision delivery. A conjugate comprises three key components: a targeting molecule, a linker, and a payload. Working together, these elements enable efficient disease-site recognition, stable systemic transport, and selective payload release, which significantly improves the therapeutic index while reducing systemic toxicity. To date, multiple conjugated drugs using monoclonal antibodies and peptides as targeting moieties have been approved globally. In recent years, a new generation of conjugates using small molecules or oligonucleotides as targeting ligands has also advanced rapidly. Beyond targeting moieties, the design of linkers and payloads has similarly shown increasing diversification.

Linkers: The Molecular Bridges Controlling Stability and Release

The linker serves as the molecular bridge connecting the targeting molecule and the drug payload, determining both stability in circulation and controlled activation within the body.

An ideal linker should remain stable during systemic circulation but cleave precisely under specific conditions, such as pH changes, enzymatic activity, or a reductive environment, to release the active drug at the intended site.

Linkers are broadly divided into cleavable and non-cleavable types. Cleavable linkers can be further categorized based on their cleavage mechanisms into acid-cleavable, enzyme-cleavable, and reduction-cleavable subtypes.

Non-cleavable linkers offer excellent stability in the bloodstream and reduced off-target effects. However, their drug release relies on internalization into target cells and subsequent lysosomal degradation, which may generate unintended metabolites before full linker cleavage occurs.

By contrast, acid-cleavable linkers, such as hydrazones and carbonates, remain stable at neutral pH but are hydrolyzed under acidic conditions found in tumor microenvironments, endosomes, or lysosomes. Although they facilitate targeted payload release in tumors, their limited plasma stability may lead to premature drug release and systemic toxicity.

In reduction-cleavable linkers, disulfide bonds are strategically employed to respond to the tumor microenvironment’s elevated glutathione (GSH) levels, typically four times higher than in normal cells, enabling controlled drug release within tumors.

Meanwhile, enzyme-cleavable linkers utilize tumor- or lysosome-specific enzymes such as matrix metalloproteinases (MMPs) and cathepsin B for selective degradation. As these enzymes are inactive in circulation, conjugates employing such linkers maintain stability in the bloodstream while enabling targeted activation in diseased tissues.

Overall, linker design is a delicate balance between efficacy and safety. It directly influences a conjugate’s half-life, selectivity, and duration of action.Key considerations include compatibility with both targeting molecule and payload, impact on ligand-receptor affinity, chemical properties affecting the payload, and ensuring that conjugation sites support efficient and specific payload release.

Drug Payloads: The Warheads That Define Therapeutic Power

The payload is the core functional unit—or “warhead”—of a drug conjugate. It is typically a highly potent molecule designed to exert therapeutic effects at the target site. Depending on the intended mechanism, conjugates can incorporate a variety of payload types:

? Cytotoxic agents: including taxane derivatives, topoisomerase inhibitors, and microtubule inhibitors, widely used in oncology.

? Radioisotopes: which, when conjugated to targeting molecules, create targeted radiotherapeutics or diagnostic imaging agents. For example, Ga-68 DOTATOC, a conjugate of gallium-68 and the somatostatin analog DOTATOC, has been approved by the U.S. FDA as a PET imaging agent for diagnosing neuroendocrine tumors.

Novartis has developed two FDA-approved radioligand therapies: Lutathera (Lu-177 dotatate) for treating somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and Pluvicto (Lu-177 vipivotide tetraxetan) for castration-resistant prostate cancer.

? Novel bioactive molecules: such as small-molecule inhibitors or modulators of signaling pathways, as well as innovative biomolecules including oligonucleotides and peptides.

These diverse payloads expand the therapeutic reach of conjugates, not only in cancer treatment but also in anti-infective and theranostic (therapy + diagnosis) applications.

By strategically matching payload type with release mechanism, conjugates can achieve high target accumulation and precise cytotoxicity, providing new therapeutic strategies for difficult-to-treat diseases. Yet, the complexity of chemical synthesis remains a significant development challenge.

With decades of experience in chemistry and drug development, WuXi AppTec provides a strong foundation for advancing next-generation modalities such as complex conjugates.

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 GalNAc-conjugated cyclic peptide 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 and formulation R&D 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’s production of high-purity peptides and GalNAc intermediates provided a solid foundation for improving solubility.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 GalNAc-conjugated cyclic peptide. 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 manufacturing costs by 71% for an 8 kg GMP batch, compared with a 1 kg GLP batch.

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：

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