▎藥明康德

編者按：靶向蛋白降解劑（TPD）通過利用細胞自身的蛋白降解系統降解與疾病相關的靶蛋白。由于無需直接抑制靶蛋白的活性，這種治療模式有望針對許多以往被認為“不可成藥”的靶點，因而成為新藥開發的熱點領域之一。早在近10年前，這項技術剛剛起步時，藥明康德就開始布局相關能力和技術，積累了豐富的成功經驗，搭建起集發現、合成、分析純化和測試等能力的一體化賦能平臺。目前，該平臺已成功支持超過120款TPD分子的開發，其中20余款順利推進至臨床階段。本文將回顧2025年上半年TPD領域的最新進展。還將介紹藥明康德的一體化CRDMO平臺如何高效解決TPD藥物開發過程中的諸多挑戰，在短短12個月內完成IND申報所需的蛋白降解靶向嵌合體（PROTAC）候選藥物的制備，并為首次人體臨床研究提供臨床試驗用藥。

臨床進展：首個PROTAC分子3期結果發布，細胞外蛋白降解療法初步臨床數據積極

今年3月，輝瑞（Pfizer）和Arvinas聯合公布了PROTAC藥物vepdegestrant的。在攜帶

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Kymera Therapeutics公司的潛在“first-in-class”口服STAT6降解劑KT-621在1期健康受試者的臨床試驗中也獲得。數據顯示，每日一次口服KT-621，在所有高于1.5 mg劑量水平中實現了平均超過90%的血液STAT6降解；在所有≥50 mg的多劑量遞增（MAD）組中，更在血液與皮膚中均達成STAT6完全降解。

百時美施貴寶（Bristol Myers Squibb）在歐洲血液學協會（EHA）年會上，展示了其靶向蛋白降解平臺的，包括其在研口服E3泛素連接酶cereblon調節劑（CELMoD）藥物mezigdomide和iberdomide在多發性骨髓瘤（MM）患者中的更新臨床研究結果，以及golcadomide在非霍奇金淋巴瘤（NHL）中的研究進展。此外，該公司也公布其潛在“first-in-class”的口服BCL6配體導向降解劑（LDD）BMS-986458在NHL中的初步研究結果。其中，golcadomide聯合利妥昔單抗治療復發/難治性濾泡性淋巴瘤患者展現出顯著療效，總緩解率（ORR）高達94%，完全緩解（CR）率為63%。BMS-986458的初步研究結果顯示，在外周血和腫瘤組織中均觀察到BCL6快速且持久的降解。從最低劑量起即觀察到在彌漫性大B細胞淋巴瘤和濾泡性淋巴瘤患者中的抗腫瘤活性。在21名可評估療效的患者中，ORR為81%（N=17），CR率為23.8%（N=5）。

Biohaven公司開發的靶向蛋白降解劑BHV-1300和近期在早期臨床試驗中表現出顯著降低細胞外蛋白的能力。這兩款在研藥物均為雙特異性分子，一端與靶蛋白結合，另一端與肝細胞表面的去唾液酸糖蛋白受體（ASGPR）結合。ASGPR可介導肝細胞通過內吞作用，將靶蛋白攝入細胞內并降解。臨床試驗數據顯示，BHV-1300和BHV-1400注射入患者體內后，短短數小時內即介導了靶蛋白的快速降解，蛋白水平降幅達到70%~80%，凸顯出這類藥物迅速的起效速度與臨床應用潛力。

融資與合作：大藥企持續布局分子膠藥物

在靶向蛋白降解領域，促進蛋白降解的雙特異性分子之外，分子膠降解劑通過與單個靶蛋白或E3泛素連接酶結合，即可誘導或穩定它們之間的相互作用，從而實現蛋白降解。這一細分領域近年來不斷升溫。在2024年，諾華（Novartis）、渤健（Biogen）、輝瑞、武田（Takeda）、衛材（Eisai）與諾和諾德（Novo Nordisk）等多家跨國藥企先后簽署了單筆數額超過10億美元的分子膠研發合作協議。

進入2025年上半年，分子膠領域的布局熱度依然持續。今年5月，基因泰克（Genentech）與Orionis Biosciences達成超過20億美元的，致力于開發靶向難以成藥靶點的小分子單價分子膠藥物，用于癌癥治療。此前在今年2月，禮來（Eli Lilly and Company）也與Magnet Biomedicine公司簽署一項近13億美元的。雙方合作的范圍不僅涵蓋基于分子膠的蛋白降解劑研發，還將探索利用分子膠促進蛋白質之間產生誘導接近和協同作用，精準靶向疾病相關組織的創新作用機制。此外，艾伯維（AbbVie）公司在1月也與Neomorph公司達成超16億美元的。

與此同時，2025年上半年，多家開發靶向蛋白降解劑的新銳公司也完成新一輪融資。具體融資及合作信息請參見下表：

▲2025年上半年靶向蛋白降解領域的融資和研發合作信息（數據來源：公開資料）

展望未來，靶向蛋白降解劑有著更為深遠的意義。這一領域的權威，丹娜-法伯癌癥研究所（Dana–Farber Cancer Institute）的Eric Fischer教授在接受

Nature Medicine

然而，TPD藥物的廣闊前景也伴隨著獨特的開發挑戰。例如，由于分子量大、結構復雜，PROTAC類分子通常存在溶解度差和藥代動力學性質不佳的問題。以下案例展示了藥明康德旗下合全藥業（WuXi STA）如何與合作伙伴攜手，有效應對這些挑戰。

解決TPD藥物開發痛點，加速創新療法進入臨床試驗

幾年前，一家公司因PROTAC分子的生產難題，選擇與合全藥業合作，希望在14個月內完成候選藥物的生產，以支持IND申請及首次人體臨床試驗。然而，該候選分子的初始合成路線非常復雜，需要多達24個步驟，且最終產率僅為0.3%。此外，PROTAC特定的分子結構進一步增加了產品結晶和純化難度。

同時，由于候選化合物分子量較大且水溶性低，其口服生物利用度只有0.9%。值得注意的是，在合成過程中還有三步涉及使用罕見金屬鈀（Pd）作為催化劑，這不僅帶來潛在安全隱患，更顯著提高了生產成本。

針對上述問題，合全藥業的工藝研發、生物催化及結晶工藝等團隊協同攻關，重新設計了一條合成路線，將合成步驟從原來的24步縮減至16步，并在其中兩個步驟中用生物催化劑替代了鈀催化劑。為攻克結晶難題，團隊采用高通量結晶篩選技術，迅速確定了符合純度與產量要求的結晶工藝，并通過優化大幅提升了生產過程的總產率。這些改進不但極大提高了整體合成工藝的可放大性，也提升了合成效率并降低了成本。

與此同時，合全藥業的制劑研發團隊針對藥物口服生物利用度低的問題，進行了全面的生物利用度增強技術篩選，最終選定噴霧干燥制備固體分散體（SDD）技術進行制劑制備。這種技術將難溶藥物以無定形狀態高度分散在聚合物中，目前已成功應用于多種上市藥物的制劑開發中。借助SDD技術，候選化合物藥片制劑的口服生物利用度提高了約30倍，為后續臨床應用奠定了堅實基礎。

合全藥業一體化CRDMO平臺的整合能力，使多個團隊能夠并行推進原料藥與制劑開發，高效協作，加速破解PROTAC分子開發中的難題。最終，團隊僅用了12個月就完成了支持IND申請所需的候選藥物生產和制劑制備，順利供應首次人體臨床研究用藥，比合作伙伴原定時間提前了2個月。

作為賦能全球靶向蛋白降解藥物開發的重要平臺之一，藥明康德一體化平臺的能力不但涵蓋PROTAC，還包括分子膠、以及多種新興雙功能性蛋白降解劑類型。例如，誘導細胞外或細胞膜蛋白進入溶酶體進行降解的溶酶體靶向嵌合體（LYTAC），將抗體與蛋白降解劑偶聯產生的蛋白降解劑-抗體偶聯藥物（DAC），誘導靶蛋白被自噬體吞噬降解的自噬靶向嵌合小分子（AUTAC），以及靶向降解特定RNA的核糖核酸酶靶向嵌合體（RIBOTAC）等。展望未來，藥明康德將繼續秉持“讓天下沒有難做的藥，難治的病”的愿景，依托全球研發基地與生產網絡，以獨特的一體化、端到端的CRDMO模式，助力靶向蛋白降解劑的開發，幫助合作伙伴將科學創新轉化為惠及全球患者的變革性藥物。

CRDMO: H1 2025 Review of Targeted Protein Degraders

Targeted protein degraders (TPDs) offer a novel therapeutic approach by leveraging the body’s own protein degradation systems to eliminate disease-associated target proteins. This strategy opens new avenues for addressing previously “undruggable” targets. Nearly a decade ago, when this technology was still in its infancy, WuXi AppTec began building relevant capabilities. Since then, the company has established a comprehensive, integrated platform encompassing discovery, synthesis, purification, analysis, and testing. To date, this platform has supported the development of more than 120 TPD molecules, with over 20 advancing to clinical stages. This article summarizes key developments in the TPD landscape during the first half of 2025. It also presents a case study demonstrating how WuXi AppTec’s integrated CRDMO platform efficiently overcomes TPD development challenges, including preparing IND-enabling materials for a proteolysis-targeting chimera (PROTAC) candidate within just 12 months for first-in-human (FIH) trials.

Clinical Advances: First PROTAC Phase 3 Results and Progress in Extracellular Protein Degraders

In March 2025, Pfizer and Arvinas jointly announced top-line results from the first-ever Phase 3 clinical trial of a PROTAC therapy—vepdegestrant. In HR+, HER2- breast cancer patients with

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Arvinas' second PROTAC candidate, ARV-102, also showed promise in Phase 1 studies, achieving significant reductions in LRRK2 protein levels in both the central nervous system and peripheral tissues of healthy volunteers—laying the groundwork for future clinical trials in LRRK2-related neurodegenerative diseases.

Meanwhile, Kymera Therapeutics reported positive Phase 1 results for KT-621, a potential first-in-class oral STAT6 degrader. Once-daily administration achieved over 90% average degradation of STAT6 in the blood at doses above 1.5 mg. Complete degradation in both blood and skin was observed in all multiple ascending dose (MAD) cohorts at doses ≥50 mg.

Bristol Myers Squibb presented its latest research on targeted protein degradation at the European Hematology Association (EHA) 2025 Congress, highlighting progress across its protein degradation platform. This included updated clinical data on its investigational oral cereblon E3 ligase modulators (CELMoDs) mezigdomide and iberdomide in patients with multiple myeloma (MM), as well as developments in the study of golcadomide in non-Hodgkin lymphoma (NHL). Additionally, the company released initial data on BMS-986458, a potential first-in-class oral BCL6 ligand-directed degrader (LDD), in NHL.

Among the findings, golcadomide in combination with rituximab demonstrated significant efficacy in patients with relapsed/refractory follicular lymphoma, with an overall response rate (ORR) of 94% and a complete response (CR) rate of 63%. Preliminary results for BMS-986458 showed rapid and sustained degradation of BCL6 in both peripheral blood and tumor tissue. Antitumor activity was observed from the lowest dose levels in patients with diffuse large B-cell lymphoma and follicular lymphoma. Among 21 evaluable patients, the ORR was 81% (N=17), with a CR rate of 23.8% (N=5).

Biohaven’s BHV-1300 and BHV-1400 demonstrated rapid and robust reductions in target protein levels—achieving 70–80% decreases within hours. These molecules bind target proteins on one end and the asialoglycoprotein receptor (ASGPR) on the other, thereby facilitating internalization and degradation via endocytosis.

Financing and Collaborations: Molecular Glues Attract Major Deals

Alongside bifunctional degraders, molecular glues—small molecules that induce or stabilize interactions between E3 ligases and target proteins—continue to draw significant interest. In 2024, multiple major pharmaceutical companies signed R&D deals for molecular glue technologies worth over $1 billion.

That momentum has carried into 2025, with several multinational pharmaceutical companies announcing collaborations focusing on molecule glue-based degraders, targeting undruggable targets in oncology, immunology, and more diseases with unmet medical needs. In addition, novel proximity-inducing mechanisms are being explored to target disease-relevant tissues with high precision.

In parallel, several emerging companies in the TPD space completed new funding rounds during H1 2025.

The potential of targeted protein degradation continues to expand. A recent article in

Nature Medicine

However, the promise of TPDs comes with unique development challenges. For example, due to their large molecular weight and structural complexity, PROTACs often suffer from poor solubility and suboptimal pharmacokinetics. The following case study illustrates how WuXi STA, an integral part of WuXi AppTec, collaborated with a partner to address these challenges effectively.

Addressing Key Bottlenecks in TPD Drug Development

Several years ago, a biotech company developing a PROTAC candidate faced synthetic challenges and turned to WuXi STA for support. The goal was to complete the production of drug substance and clinical trial material within 14 months to support an IND filing and FIH trial. However, the original synthesis route involved 24 steps and yielded only 0.3%. Crystallization and purification proved difficult due to the compound’s unique structure.

Compounding the challenge, the candidate’s high molecular weight and poor solubility resulted in oral bioavailability of just 0.9%. Moreover, three steps in the synthesis relied on a palladium (Pd) catalyst, raising safety concerns and increasing production costs.

To resolve these issues, WuXi STA’s process chemistry, biocatalysis, and crystallization teams worked in concert to redesign the synthesis route, reducing the number of steps from 24 to 16 and replacing palladium with biocatalysts in two steps. To tackle crystallization bottlenecks, high-throughput crystallization screening identified suitable conditions that met both purity and yield requirements. These changes significantly improved the scalability and efficiency of the synthetic route while reducing costs.

Simultaneously, WuXi STA’s formulation team addressed the low oral bioavailability by exploring a range of enabling technologies and ultimately selected spray-dried dispersion (SDD) to prepare a solid dosage form. SDD disperses poorly soluble compounds in an amorphous state within a polymer matrix and has been successfully used in several approved drugs. With this approach, the candidate’s oral bioavailability improved by approximately 30-fold—supporting further clinical advancement.

Thanks to WuXi STA’s integrated CRDMO model, API process development and formulation were advanced in parallel by multiple teams working seamlessly together. Ultimately, they delivered IND-enabling materials and clinical trial materials within just 12 months—two months ahead of schedule.

As one of the industry’s leading platforms enabling targeted protein degradation, WuXi AppTec’s integrated services extend beyond PROTACs to a wide array of bifunctional modalities, including:

? LYTACs (lysosome-targeting chimeras): for degrading extracellular or membrane proteins via lysosomes

? DACs (degrader-antibody conjugates): combining antibodies with protein degraders

? AUTACs (autophagy-targeting chimeras): small molecules inducing autophagic degradation

? RIBOTACs (ribonuclease-targeting chimeras): targeting and degrading specific RNA sequences

As targeted protein degradation continues to evolve, WuXi STA remains committed to leveraging its integrated CRDMO platform to empower the development of targeted protein degraders, helping partners translate scientific innovation into transformative medicines for patients around the world.

參考資料：

[1] Induced proximity pushes beyond protein degraders, as first RIPTAC moves into the clinic. Retrieved May 15, 2025, from https://www.nature.com/articles/d41573-025-00037-7

[2] Monte Rosa Therapeutics Announces Fourth Quarter 2024 Financial Results and Provides Corporate Update Including New Clinical Results from MRT-6160 and MRT-2359 Programs. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/03/20/3046104/0/en/Monte-Rosa-Therapeutics-Announces-Fourth-Quarter-2024-Financial-Results-and-Provides-Corporate-Update-Including-New-Clinical-Results-from-MRT-6160-and-MRT-2359-Programs.html

[3] Magnet Biomedicine Enters into a Collaboration and License Agreement with Lilly to Discover and Develop Novel Molecular Glue Medicines. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/magnet-biomedicine-enters-into-a-collaboration-and-license-agreement-with-lilly-to-discover-and-develop-novel-molecular-glue-medicines-302387756.html

[4] AbbVie and Neomorph Announce Collaboration to Develop Molecular Glue Degraders for Oncology and Immunology. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/abbvie-and-neomorph-announce-collaboration-to-develop-molecular-glue-degraders-for-oncology-and-immunology-302357741.html

[5] Arvinas Presents First-in-Human Data for Investigational Oral PROTAC ARV-102 Demonstrating Blood-Brain Barrier Penetration, and Central and Peripheral LRRK2 Degradation. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/04/04/3055854/0/en/Arvinas-Presents-First-in-Human-Data-for-Investigational-Oral-PROTAC-ARV-102-Demonstrating-Blood-Brain-Barrier-Penetration-and-Central-and-Peripheral-LRRK2-Degradation.html

[6] Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/03/11/3040386/0/en/Arvinas-and-Pfizer-Announce-Positive-Topline-Results-from-Phase-3-VERITAC-2-Clinical-Trial.html

[7] Argobio and the Institut Pasteur launch Enodia Therapeutics: A biotech company with a new approach for Targeted protein Degradation. Retrieved May 15, 2025, from https://www.pasteur.fr/en/press-area/press-documents/argobio-and-institut-pasteur-launch-enodia-therapeutics-biotech-company-new-approach-targeted

[8] Biohaven Reports Positive Degrader Data Achieving > 80% Sustained Reductions in Total IgG with Potential First-in-Class BHV-1300. Retrieved May 15, 2025, from https://ir.biohaven.com/news-releases/news-release-details/biohaven-reports-positive-degrader-data-achieving-80-sustained

[9] Revolution Medicines Reports First Quarter 2025 Financial Results and Update on Corporate Progress. Retrieved May 15, 2025, from https://ir.revmed.com/node/11636

[10] Photys Therapeutics Enters into Exclusive License Agreement with Polymed for Phase 1-Ready IRAK4 Degrader, Furthering its Proximity-based Pipeline and Mission. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/02/20/3029603/0/en/Photys-Therapeutics-Enters-into-Exclusive-License-Agreement-with-Polymed-for-Phase-1-Ready-IRAK4-Degrader-Furthering-its-Proximity-based-Pipeline-and-Mission.html

[11] Nurix Licenses a Drug Discovery Program to Sanofi Targeting a Novel Transcription Factor for Autoimmune Diseases. Retrieved May 15, 2025, from https://ir.nurixtx.com/news-releases/news-release-details/nurix-licenses-drug-discovery-program-sanofi-targeting-novel

[12] PAQ Therapeutics Announces $39 Million Series B Financing and Initiates Phase 1 Trial to Advance Novel Approach Addressing KRAS-Driven Cancers with High Unmet Need. Retrieved May 15, 2025, from https://www.prnewswire.com/news-releases/paq-therapeutics-announces-39-million-series-b-financing-and-initiates-phase-1-trial-to-advance-novel-approach-addressing-kras-driven-cancers-with-high-unmet-need-302447786.html

[13] Fraser Therapeutics Secures $29 Billion Series B from J&J and 8 Others. Retrieved May 15, 2025, from http://prazertx.com/pages/board/view.php?menu_code=477&board_sid=16&data_sid=261&page_num=&skey=&sval=&category_code1=

[14] TRIMTECH Therapeutics raises $31M seed funding to advance targeted protein degradation pipeline for treatment of neurodegenerative diseases. Retrieved May 15, 2025, from https://www.businesswire.com/news/home/20250305069531/en/TRIMTECH-Therapeutics-raises-%2431M-seed-funding-to-advance-targeted-protein-degradation-pipeline-for-treatment-of-neurodegenerative-diseases

[15] Auron Therapeutics Announces FDA Clearance to Initiate Clinical Development of AUTX-703 and Completion of Series B Financing. Retrieved May 15, 2025, from https://www.globenewswire.com/news-release/2025/02/04/3020131/0/en/Auron-Therapeutics-Announces-FDA-Clearance-to-Initiate-Clinical-Development-of-AUTX-703-and-Completion-of-Series-B-Financing.html

[16] Advancing targeted protein degraders: leveraging CMC strategies for rapid IND submission and bioavailability solutions. Retrieved May 15, 2025, from https://sta.wuxiapptec.com/wp-content/uploads/2024/10/Advancing-targeted-protein-degraders.pdf

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