同行致遠 | ASH年會盤點，新一代蛋白降解療法公布最新進展 | Bilingual

編者按：第67屆美國血液學會（ASH）年會在美國奧蘭多落下帷幕。ASH年會是全球規模最大的血液疾病學術會議之一，本屆年會上，多家生物醫藥公司匯報了靶向蛋白降解治療血液癌癥的最新臨床試驗結果。靶向蛋白降解已經在治療血液癌癥領域得到廣泛應用，獲批治療多發性骨髓瘤的來那度胺（lenalidomide）和泊馬度胺（pomalidomide）均利用了靶向蛋白降解的作用機制。在靶向蛋白降解療法的產業轉化歷程中，藥明康德幾乎全程參與，為合作伙伴提供一體化賦能。在蛋白降解靶向嵌合體（PROTAC?）剛剛起步時，藥明康德就前瞻性地布局了相關能力和技術，搭建了集發現、合成、分析純化和測試等能力于一體的一體化賦能平臺，助力全球合作伙伴高效推進藥物從早期發現到臨床試驗階段。伴隨著新型靶向蛋白降解技術的持續涌現，藥明康德緊跟科學前沿，迅速構建相關技術平臺，如今能力已涵蓋PROTAC?、分子膠、AUTAC、LYTAC、DUBTAC、RIBOTAC、PHICS以及DAC等主要分子類型。本文將與讀者分享在ASH年會上公布的靶向蛋白降解藥物的部分最新研發進展。

百時美施貴寶公布多款靶向蛋白降解療法最新結果

在ASH年會上，百時美施貴寶（Bristol Myers Squibb）公布了旗下多款靶向蛋白降解藥物的最新臨床試驗結果。其中，golcadomide（GOLCA）是一款潛在“first-in-class”口服CELMoD藥物，它通過與E3泛素連接酶復合體中的cereblon結合，導致對IKZF1和IKZF3蛋白的快速和深度降解，從而達到殺傷骨髓瘤細胞和調節免疫系統的作用。

ASH摘要顯示，golcadomide與利妥昔單抗、環磷酰胺、阿霉素、長春新堿和潑尼松（R-CHOP）聯用，在治療初治B細胞淋巴瘤患者的1b期臨床試驗中獲得積極結果。在可評估療效的患者中，0.4 mg劑量組患者在治療結束時的完全代謝緩解率（CMR）為88%，在高風險患者亞群中，這一數值為89%。在中位隨訪時間為24個月時，0.4 mg劑量組患者的24個月無進展生存率為79%，24個月總生存率為85.3%。

此外，golcadomide與利妥昔單抗聯用，在治療接受過多種前期治療的復發/難治性（R/R）彌漫性大B細胞淋巴瘤（DLBCL）患者的1/2期臨床試驗中也獲得積極結果。摘要數據顯示，在可評估療效的患者中，0.2 mg劑量組的總緩解率（ORR）為34%，完全緩解率（CR）為20%；0.4 mg劑量組的ORR為58%，CR為44%。

在與利妥昔單抗聯用治療R/R濾泡性淋巴瘤（FL）的期臨床試驗中，接受golcadomide治療患者的ORR為97%，CR為78%。

百時美施貴寶旗下的BMS-986397是一款靶向CK1α的潛在“first-in-class”蛋白降解劑。在治療R/R急性髓系白血病（AML）和高危骨髓增生異常綜合征（HR-MDS）的1期臨床試驗中，BMS-986397在治療R/R HR-MDS時達到57.1%的完全緩解率，在治療R/R AML時的ORR為12.1%。

該公司的BMS-986458是一款潛在“first-in-class”靶向降解BCL6的雙功能配體介導降解劑。數據顯示，在治療R/R非霍奇金淋巴瘤（NHL）患者的1期臨床試驗中，ORR達到65%，CR為21%。在DLBCL患者亞群中的ORR為54%，CR為7%；在FL患者亞群中的ORR為80%，CR為40%。

克服布魯頓氏酪氨酸激酶抑制劑耐藥性，蛋白降解劑展現抗癌潛力

布魯頓氏酪氨酸激酶（BTK）抑制劑是多種B細胞血液癌癥的重要治療選擇。然而BTK抑制劑耐藥性的出現，以及BTK不依賴于激酶活性介導信號傳導的功能，揭示了采用其它手段靶向BTK蛋白功能的重要性。靶向BTK的蛋白降解劑通過直接誘導BTK蛋白被蛋白酶體降解，為克服BTK抑制劑耐藥性提供了有效策略。在ASH年會上，多家公司展示了靶向BTK的蛋白降解劑在治療多種BTK抑制劑耐藥血液腫瘤方面的療效。

Nurix Therapeutics公司開發的bexobrutideg（NX-5948）是一款創新BTK降解劑。數據顯示，在治療R/R慢性淋巴細胞白血病（CLL）患者的1a期臨床試驗中，在47名可進行療效評估的患者中，接受bexobrutideg治療的患者的ORR達到83%，中位無進展生存期為22.1個月，中位緩解持續時間為20.1個月。值得一提的是，這些患者此前接受過多種治療，包括共價和/或非共價BTK抑制劑。在1b期患者隊列中，早期數據顯示接受劑量為600 mg的bexobrutideg治療的患者ORR為83.3%。該公司計劃選用每天600 mg的劑量進行下一步開發。

Bexobrutideg在治療接受過多種前期治療的華氏巨球蛋白血癥（Waldenstr?m macroglobulinemia，WM）患者的1期臨床試驗中也表現出抗癌活性。在28名可評估療效的WM患者中，ORR達到75%。

百濟神州（BeOne Medicines）也在ASH年會上公布了其BTK降解劑BGB-16673的臨床試驗結果。在治療R/R慢性淋巴細胞白血病/小淋巴細胞淋巴瘤患者的1期臨床試驗中，數據顯示，患者的ORR達到85.3%，其中接受劑量為200 mg的BGB-16673治療的患者亞群的ORR達到94.4%。在既往接受過共價BTK抑制劑和BCL2抑制劑治療的患者中，ORR為93.2%。

在治療WM患者的臨床試驗中，BGB-16673達到85.7%的ORR。12個月無進展生存率為78.3%。

多款分子膠降解劑臨床結果公布

針對IKZF1和IKZF3這兩個在多發性骨髓瘤中已經被驗證的靶點，多家公司也在開發新一代分子膠降解劑。在ASH年會上，標新生物公布了在研分子膠降解劑GT919的最新臨床試驗結果。摘要顯示，在治療R/R多發性骨髓瘤患者的1期臨床試驗中，接受劑量超過2 mg GT919治療的患者ORR達到36%，中位隨訪時間為5.2個月時，中位無進展生存期和緩解持續時間尚未達到。

GluBio Therapeutics公司也公布了靶向降解IKZF1和IKZF3的在研療法GLB-002的1期臨床試驗結果。摘要顯示，在R/R NHL患者中，GLB-002達到61.5%的ORR，觀察到的最長緩解持續時間達到495天。接受2期臨床試驗推薦劑量GLB-002治療的患者的ORR達到73.3%，CR為20%。

CRDMO一體化賦能蛋白降解療法開發

作為全球醫藥創新的賦能者，藥明康德不僅見證了靶向蛋白降解領域的快速發展，也依托其一體化、端到端的CRDMO平臺，助力合作伙伴解鎖靶向蛋白降解的更多可能。

在今年接受行業媒體時，藥明康德聯席首席執行官楊青博士指出，在賦能全球客戶的過程中，藥明康德已合成了超過18.8萬種復雜的靶向蛋白降解化合物，其中70多種已進入臨床前候選藥物階段，10多種已進入后期開發階段。

展望未來，藥明康德將持續以一體化、端到端的CRDMO賦能平臺，助力全球合作伙伴加速創新藥物的研發生產進程，讓科學突破更快為患者帶來福祉。

ASH: New Generation of Targeted Protein Degraders Show Potential in Hematologic Malignancies

The 67th American Society of Hematology (ASH) Annual Meeting concluded in Orlando, USA. As one of the world’s largest academic conferences in hematologic diseases, ASH served as a major platform for scientific exchange. This year, multiple biopharmaceutical companies presented new clinical results on targeted protein degradation (TPD) for hematologic malignancies. Targeted protein degradation has already demonstrated broad clinical value in this field. Both lenalidomide and pomalidomide, approved for treating multiple myeloma (MM), operate through this mechanism.

When TPD technology was still in its infancy, WuXi AppTec started building relevant capabilities. Since then, the company has established a comprehensive, integrated platform encompassing discovery, synthesis, purification, analysis, and testing. This article highlights several important development updates disclosed at this year’s ASH meeting.

Targeting IKZF1 and IKZF3, New Generation of Molecular Glue Degraders Show Clinical Potential

IKZF1 and IKZF3 are clinically validated, crucial transcription factors in multiple myeloma, targeted by approved Immunomodulatory Drugs (IMiDs) such as lenalidomide and pomalidomide. Building on their success, many biopharmaceutical companies are developing next-generation molecular glue degraders targeting IKZF1 and IKZF3.

At the ASH meeting, multiple such molecular glue degraders showed promising clinical results. For example, a potential first-in-class oral CELMoD molecule, combined with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), generated encouraging results in treatment-na?ve B-cell lymphoma patients in an early-stage clinical trial. Among evaluable patients, the complete metabolic response (CMR) rate at the end of treatment in the 0.4 mg cohort reached 88%, and 89% in the high-risk subgroup. With a median follow-up of 24 months, the 24-month progression-free survival (PFS) rate was 79%, and the 24-month overall survival (OS) rate was 85.3%.

In a Phase 1 trial in relapsed/refractory (R/R) multiple myeloma, another IKZF1/3 targeting molecular glue degrader demonstrated an overall response rate (ORR) of 36%. Treating R/R non-Hodgkin lymphoma (NHL), an IKZF1/3-targeting molecular glue degrader achieved an ORR of 61.5% in a Phase 1 trial, with the longest observed duration of response reaching 495 days. Among patients treated at the recommended Phase 2 dose, the ORR was 73.3%, with 20% achieving complete response.

Addressing BTK Inhibitor Resistance: Protein Degraders Show Meaningful Potential

Bruton tyrosine kinase (BTK) inhibitors remain an essential therapy for many B-cell malignancies. However, resistance and kinase-independent signaling reveal the need for additional strategies. BTK protein degraders offer such an approach by inducing proteasomal degradation of BTK, potentially overcoming resistance to both covalent and non-covalent BTK inhibitors.

At ASH, encouraging data were shared for multiple BTK degraders. In multiple early-stage clinical trials, BTK degraders reached an ORR of above 80% in relapsed/refractory chronic lymphocytic leukemia (CLL) patients who were heavily pretreated, including covalent and/or non-covalent BTK inhibitors.

BTK degraders also demonstrated encouraging antitumor activity in Waldenstr?m macroglobulinemia (WM) patients, achieving an ORR around 80% in early clinical trials.

Integrated CRDMO Platform Enables Protein Degrader Development

For years, WuXi AppTec has supported partners worldwide across discovery, development, and manufacturing through its unique integrated, end-to-end CRDMO model, accelerating the advancement of breakthrough therapies to patients.

From the earliest days of PROTAC?, WuXi AppTec strategically invested in relevant technologies, building a platform that integrates discovery, synthesis, purification, and testing to help global partners efficiently advance programs from early-stage research into clinical trials. As new modalities—including molecular glues, AUTAC, LYTAC, DUBTAC, RIBOTAC, PHICS, and DAC—have emerged, WuXi AppTec has rapidly expanded its capabilities to remain at the cutting edge of science.

In an interview with STAT this year, Dr. Steve Yang, Co-CEO of WuXi AppTec, noted that WuXi AppTec had synthesized more than 188,000 complex targeted protein degrader compounds, with more than 70 advancing to preclinical candidate (PCC) status and over 10 entering late-stage development.

Looking ahead, WuXi AppTec will continue leveraging its integrated, end-to-end CRDMO platform to unlock new possibilities and bring transformative therapies to patients with cancer and other diseases worldwide.

參考資料：

[1] Updated Efficacy and Safety Results of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients With Relapsed/Refractory Waldenstr?m Macroglobulinemia From the Ongoing Phase 1 CaDAnCe-101 Study. Retrieved December 8, 2025, from https://beonemedaffairs.com/us/wp-content/uploads/sites/11/2025/12/ASH2025_phase-1-cadance-101-updated-results-of-btk-degrader-bgb-16673-in-rr-wm.pdf

[2] Nurix Therapeutics Presents New Data from the Phase 1 Trial of Bexobrutideg (NX-5948) in Waldenstr?m Macroglobulinemia at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition. Retrieved December 8, 2025, from https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-presents-new-data-phase-1-trial-bexobrutideg

[3] Abstract Title : Discovery of first-in-class calr-targeted precision ADCs delivering a CDK9degrader payload for the treatment of calr-mutated MPNs. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/300024

[4] BMS-986397, a first-in-class casein kinase 1α (CK1α) degrader in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HRMDS): A phase 1 dose escalation study. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/297636

[5] GT919, a novel IKZF3/1 molecular glue degrader: Phase 1 safety and preliminary efficacy in relapsed or refractory multiple myeloma (R/R MM). Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/299089

[6] Amx-883, a potent and selective degrader of BRD9 drives differentiation in acute myeloid leukaemia and shows synergistic efficacy in combination with venetoclax In Vivo and prevents the emergence of resistance to venetoclax in vitro. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/291003

[7] BMS-986397, a first-in-class casein kinase 1α (CK1α) degrader in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HRMDS): A phase 1 dose escalation study. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/297636

[8] BMS-986458, a first-in-class, bifunctional cereblon-dependent ligand-directed degrader of B-cell lymphoma 6 (BCL6) in patients with Relapsed/Refractory (R/R) non-Hodgkin lymphoma (NHL): Updated results from the Phase 1 dose escalation study. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/299984

[9] Updated Efficacy and Safety Results of the Bruton Tyrosine Kinase Degrader BGB-16673 in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma From the Ongoing Phase 1 CaDAnCe-101 Study. Retrieved December 8, 2025, from https://beonemedaffairs.com/us/wp-content/uploads/sites/11/2025/12/ASH2025_phase-1-cadance-101-study-btk-degrader-bgb-16673-in-rr-cll-sll.pdf

[10] Preliminary results of a first-in-human, Phase 1 study of GLB-002, a novel molecular glue degrader of IKZF1/3, in patients with relapsed or refractory non-Hodgkin lymphoma. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/296618

[11] Nurix Therapeutics Presents New Data Demonstrating Durable, Deepening Responses in Phase 1 Trial of Bexobrutideg (NX-5948) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) at the 67th American Society of Hematology (ASH) Annual Meeting & Exposition. Retrieved December 8, 2025, from https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-presents-new-data-demonstrating-durable

[12] Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD? agent, plus R-CHOP in patients (Pts) with previously untreated aggressive B-cell lymphoma (a-BCL): 24-month efficacy Results. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/297038

[13] Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD? agent, ± rituximab (R) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): Phase 1/2 study extended follow-up Results. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/297009

[14] Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD? agent, ± rituximab (R) in patients with Relapsed/Refractory follicular lymphoma (R/R FL): Phase 1/2 study extended follow-up Results. Retrieved December 4, 2025, from https://meetings-api.hematology.org/api/abstract/vmpreview/296971

[15] Bristol Myers Squibb Advances Lymphoma Research with New Targeted Protein Degradation and Cell Therapy Data at ASH 2025. Retrieved December 8, 2025, from https://www.businesswire.com/news/home/20251208095739/en/Bristol-Myers-Squibb-Advances-Lymphoma-Research-with-New-Targeted-Protein-Degradation-and-Cell-Therapy-Data-at-ASH-2025

免責聲明：本文僅作信息交流之目的，文中觀點不代表藥明康德立場，亦不代表藥明康德支持或反對文中觀點。本文也不是治療方案推薦。如需獲得治療方案指導，請前往正規醫院就診。

版權說明：歡迎個人轉發至朋友圈，謝絕媒體或機構未經授權以任何形式轉載至其他平臺。轉載授權請在「藥明康德」微信公眾號回復“轉載”，獲取轉載須知。