同行致遠(yuǎn) | 一體化平臺(tái)加速分子膠降解劑進(jìn)入臨床試驗(yàn) | Bilingual

編者按：近年來，分子膠作為一種新興治療模式，在藥物發(fā)現(xiàn)和開發(fā)領(lǐng)域受到廣泛關(guān)注。它們通過促使兩種蛋白特異性結(jié)合而發(fā)揮作用，為攻克眾多傳統(tǒng)手段難以觸達(dá)的致病蛋白提供了新策略。目前，全球已有超過100款分子膠藥物進(jìn)入臨床開發(fā)階段。其中，分子膠降解劑通過與E3泛素連接酶結(jié)合，調(diào)節(jié)泛素連接酶與底物蛋白的結(jié)合界面，誘導(dǎo)特定靶點(diǎn)蛋白發(fā)生降解。作為全球醫(yī)藥創(chuàng)新的賦能者，藥明康德長期以來，通過獨(dú)特的一體化、端到端CRDMO模式，持續(xù)助力包括分子膠降解劑在內(nèi)的創(chuàng)新藥物加速從實(shí)驗(yàn)室來到患者身邊。本文將以一項(xiàng)實(shí)際合作項(xiàng)目為例，展示這一平臺(tái)如何加速分子膠降解劑的臨床前開發(fā)過程。

在最近的一項(xiàng)合作中，一家生物技術(shù)公司找到藥明康德旗下合全藥業(yè)，希望助力其將一款創(chuàng)新分子膠降解劑推進(jìn)至首個(gè)人體臨床試驗(yàn)。項(xiàng)目啟動(dòng)后，合全藥業(yè)的原料藥工藝開發(fā)團(tuán)隊(duì)和制劑研發(fā)團(tuán)隊(duì)幾乎同步開始研發(fā)工作。原料藥團(tuán)隊(duì)在4個(gè)月內(nèi)完成了GLP批次（1公斤規(guī)模）的藥物合成，為隨后的毒理學(xué)研究提供了充分材料。與此同時(shí)，制劑研發(fā)團(tuán)隊(duì)也快速推進(jìn)處方前研究，篩選適用于藥代動(dòng)力學(xué)、藥效學(xué)和毒理學(xué)研究的臨床前制劑。

由于分子膠類化合物特殊的分子結(jié)構(gòu)通常導(dǎo)致藥物水溶性較差，提升溶解度是確保體內(nèi)暴露水平和生物利用度的關(guān)鍵。為此，處方前制劑開發(fā)團(tuán)隊(duì)在短短8周內(nèi)考察了溶液制劑、混懸制劑、噴霧干燥分散體（SDD）制劑、脂質(zhì)微乳（LBF）制劑和納米制劑等多種策略。最終，SDD技術(shù)脫穎而出，SDD制劑將該分子的體內(nèi)生物利用度提高了4倍，顯著推動(dòng)了項(xiàng)目進(jìn)度。

針對(duì)該項(xiàng)目，如果原料藥合成團(tuán)隊(duì)、制劑研發(fā)團(tuán)隊(duì)和分析團(tuán)隊(duì)依次線性完成原料藥生產(chǎn)、制劑研發(fā)以及臨床試驗(yàn)藥品的制備，整個(gè)流程大約需要60周，但憑借一體化平臺(tái)優(yōu)勢(shì)，各團(tuán)隊(duì)全程無縫銜接、并行協(xié)作，最終在42周內(nèi)將這款分子膠降解劑從臨床前候選藥物提名推進(jìn)至IND申請(qǐng)，為合作伙伴節(jié)省了大約30%的開發(fā)時(shí)間。

值得一提的是，在進(jìn)入GMP生產(chǎn)之前，檢測發(fā)現(xiàn)原料藥的結(jié)晶產(chǎn)物中出現(xiàn)意外新晶型。由于晶型差異可能顯著影響藥物穩(wěn)定性、溶解度以及溶出速率，進(jìn)而影響生物利用度和臨床療效。因此，有必要盡快查明原因并加以解決。

合全藥業(yè)的多個(gè)團(tuán)隊(duì)共同合作，僅用4周完成對(duì)藥物不同晶型的再次表征，針對(duì)最穩(wěn)定晶型重新開發(fā)了結(jié)晶和噴霧干燥工藝。同時(shí)，制劑研發(fā)團(tuán)隊(duì)在開展SDD制劑開發(fā)之前確認(rèn)目標(biāo)晶型在溶液中的穩(wěn)定性和溶解度，確保后續(xù)制劑開發(fā)的順利進(jìn)行。

上述案例僅是藥明康德賦能分子膠開發(fā)的一個(gè)縮影。依托其一體化平臺(tái)，藥明康德已構(gòu)建覆蓋分子膠藥物發(fā)現(xiàn)、開發(fā)和生產(chǎn)的全周期綜合解決方案。藥明康德的分子膠發(fā)現(xiàn)平臺(tái)通過將親和篩選質(zhì)譜（ASMS）與高通量篩選（HTS）等多維篩選技術(shù)與多樣化的DNA編碼化合物庫（DEL）深度結(jié)合，打破了單一篩選方式的限制，讓更多不同類型的靶點(diǎn)進(jìn)入分子膠研究視野，進(jìn)一步拓展了分子膠在更廣泛靶點(diǎn)類型上的開發(fā)潛力。

在原料藥開發(fā)方面，合全藥業(yè)有包括結(jié)晶工藝、金屬催化等在內(nèi)的專業(yè)性極強(qiáng)的原料藥工藝開發(fā)技術(shù)平臺(tái)，為分子膠等復(fù)雜分子開發(fā)提供穩(wěn)定可靠的工藝支持。僅在2024年，公司的結(jié)晶團(tuán)隊(duì)就支持了800多個(gè)化合物的工藝開發(fā)，其中包括190步的后期和商業(yè)化結(jié)晶工藝開發(fā)。

在制劑開發(fā)方面，合全藥業(yè)的生物利用度增溶技術(shù)平臺(tái)包括噴霧干燥、熱熔擠出、脂質(zhì)納米顆粒、納米懸浮、液體膠囊等多種提高藥物溶解度的技術(shù)，適配多類難溶小分子化合物，包括分子膠類候選藥物。

今年發(fā)表在

Nature Biotechnology

An Integrated Platform Accelerates a Molecular Glue Degrader into Clinical Trials

Molecular glues have emerged as a promising new therapeutic modality and are gaining increasing attention in drug discovery and development. These small molecules induce or stabilize protein–protein interactions (PPIs), enabling degradation or modulation of challenging targets. This unique mechanism offers a new strategy for addressing disease-causing proteins that are difficult to inhibit using traditional small-molecule approaches. Today, more than 100 molecular glue programs have entered clinical trials. As a global enabler of pharmaceutical innovation, WuXi AppTec supports such programs through its integrated, end-to-end CRDMO platform, helping accelerate the journey of innovative molecules from laboratory research to clinical evaluation. The collaboration highlighted below demonstrates how this integrated approach can shorten preclinical development timelines.

In a recent collaboration, a biotechnology company partnered with WuXi STA to advance an innovative molecular glue degrader to its first-in-human clinical trial. Shortly after initiation, the drug substance process development team and the drug product formulation team began work in parallel.Within four months, the drug substance team successfully produced a 1-kg GLP batch to support toxicology studies.At the same time, the formulation team advanced pre-formulation studies to identify candidate formulations suitable for pharmacokinetic, pharmacodynamic, and toxicology evaluations.

Because molecular glue compounds typically exhibit poor aqueous solubility, improving dissolution and bioavailability was a key development priority. Over an eight-week period, the pre-formulation team evaluated multiple solubility-enhancement strategies, including solution formulations, nano suspensions, spray-dried dispersions (SDD), lipid-based emulsion and nano particles.The SDD strategy was ultimately selected, resulting in a fourfold improvement in bioavailability and significantly accelerating project progress.

The advantages of WuXi STA’s integrated platform became increasingly evident as development progressed.The drug substance, formulation, and analytical teams worked concurrently, enabling the molecule to advance from preclinical candidate nomination to IND submission in 42 weeks.By comparison, performing these activities sequentially could have extended the timeline to approximately 60 weeks. Thus,WuXi STA’s integrated model provided an estimated 30% reduction in development time.

Before transitioning to GMP manufacturing, analytical testing identified an unexpected crystal form in the drug substance. Because polymorphic differences can affect stability, solubility, dissolution rate, bioavailability, and ultimately clinical performance, quickly resolving the issue was essential.Through close cross-team collaboration, WuXi STA completed polymorph re-characterization and the development of crystallization and spray-drying processes targeting the most stable form within four weeks. In parallel, the formulation team verified the solubility and stability of the target crystal form in solution prior to initiating SDD development, ensuring a smooth transition into subsequent formulation activities.

This collaboration represents just one example of how WuXi AppTec supports molecular glue drug development. The company’s discovery platform integrates affinity selection mass spectrometry (ASMS), high-throughput screening (HTS), and diverse DNA-encoded libraries (DELs), expanding target possibilities beyond what traditional screening approaches can achieve.

For API process development, WuXi STA operates a comprehensive technology platform that includes specialized capabilities in Crystallization & Particle Engineering, Chemo Catalysis, and more. This platform delivers critical support for complex molecule development, including molecular glue candidates. In 2024 alone, the crystallization team supported the development of more than 800 compounds, encompassing 190 late-stage and commercial steps.

On the formulation side, WuXi STA’s bioavailability enhancement platform provides multiple solubility-improving technologies: including spray-drying, hot-melt extrusion, lipid nanoparticles, nano-suspensions, and liquid-filled capsules, to support a wide range of poorly soluble small molecules, including molecular glue candidates.

A recent article published in

Nature Biotechnology

參考資料：

[1] The Rise of Molecular Glues: Transforming Protein-Protein Interactions into Therapeutic Opportunities. Retrieved October 23, 2025, from https://www.delveinsight.com/blog/rise-of-molecular-glues

[2] 處方前研究. Retrieved October 23, 2025, from https://sta.wuxiapptec.com/cn/services-solutions/drug-product/oral-drug-product/developability-formulation-research/

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