编者按：第67届美国血液学会(ASH)年会在美国奥兰多落下帷幕。ASH年会是全球规模最大的血液疾病学术会议之一，本届年会上，多家生物医药公司汇报了靶向蛋白降解治疗血液癌症的最新临床试验结果。靶向蛋白降解已经在治疗血液癌症领域得到广泛应用，获批治疗多发性骨髓瘤的来那度胺(lenalidomide)和泊马度胺(pomalidomide)均利用了靶向蛋白降解的作用机制。在靶向蛋白降解疗法的产业转化历程中，药明康德几乎全程参与，为合作伙伴提供一体化赋能。在蛋白降解靶向嵌合体(PROTAC®)刚刚起步时，药明康德就前瞻性地布局了相关能力和技术，搭建了集发现、合成、分析纯化和测试等能力于一体的一体化赋能平台，助力全球合作伙伴高效推进药物从早期发现到临床试验阶段。伴随着新型靶向蛋白降解技术的持续涌现，药明康德紧跟科学前沿，迅速构建相关技术平台，如今能力已涵盖PROTAC®、分子胶、AUTAC、LYTAC、DUBTAC、RIBOTAC、PHICS以及DAC等主要分子类型。本文将与读者分享在ASH年会上公布的靶向蛋白降解药物的部分最新研发进展。

百时美施贵宝公布多款靶向蛋白降解疗法最新结果

在ASH年会上，百时美施贵宝(Bristol Myers Squibb)公布了旗下多款靶向蛋白降解药物的最新临床试验结果。其中，golcadomide(GOLCA)是一款潜在“first-in-class”口服CELMoD药物，它通过与E3泛素连接酶复合体中的cereblon结合，导致对IKZF1和IKZF3蛋白的快速和深度降解，从而达到杀伤骨髓瘤细胞和调节免疫系统的作用。

ASH摘要显示，golcadomide与利妥昔单抗、环磷酰胺、阿霉素、长春新碱和泼尼松(R-CHOP)联用，在治疗初治B细胞淋巴瘤患者的1b期临床试验中获得积极结果。在可评估疗效的患者中，0.4 mg剂量组患者在治疗结束时的完全代谢缓解率(CMR)为88%，在高风险患者亚群中，这一数值为89%。在中位随访时间为24个月时，0.4 mg剂量组患者的24个月无进展生存率为79%，24个月总生存率为85.3%。

此外，golcadomide与利妥昔单抗联用，在治疗接受过多种前期治疗的复发/难治性(R/R)弥漫性大B细胞淋巴瘤(DLBCL)患者的1/2期临床试验中也获得积极结果。摘要数据显示，在可评估疗效的患者中，0.2 mg剂量组的总缓解率(ORR)为34%，完全缓解率(CR)为20%;0.4 mg剂量组的ORR为58%，CR为44%。

在与利妥昔单抗联用治疗R/R滤泡性淋巴瘤(FL)的期临床试验中，接受golcadomide治疗患者的ORR为97%，CR为78%。

百时美施贵宝旗下的BMS-986397是一款靶向CK1α的潜在“first-in-class”蛋白降解剂。在治疗R/R急性髓系白血病(AML)和高危骨髓增生异常综合征(HR-MDS)的1期临床试验中，BMS-986397在治疗R/R HR-MDS时达到57.1%的完全缓解率，在治疗R/R AML时的ORR为12.1%。

该公司的BMS-986458是一款潜在“first-in-class”靶向降解BCL6的双功能配体介导降解剂。数据显示，在治疗R/R非霍奇金淋巴瘤(NHL)患者的1期临床试验中，ORR达到65%，CR为21%。在DLBCL患者亚群中的ORR为54%，CR为7%;在FL患者亚群中的ORR为80%，CR为40%。

克服布鲁顿氏酪氨酸激酶抑制剂耐药性，蛋白降解剂展现抗癌潜力

布鲁顿氏酪氨酸激酶(BTK)抑制剂是多种B细胞血液癌症的重要治疗选择。然而BTK抑制剂耐药性的出现，以及BTK不依赖于激酶活性介导信号传导的功能，揭示了采用其它手段靶向BTK蛋白功能的重要性。靶向BTK的蛋白降解剂通过直接诱导BTK蛋白被蛋白酶体降解，为克服BTK抑制剂耐药性提供了有效策略。在ASH年会上，多家公司展示了靶向BTK的蛋白降解剂在治疗多种BTK抑制剂耐药血液肿瘤方面的疗效。

Nurix Therapeutics公司开发的bexobrutideg(NX-5948)是一款创新BTK降解剂。数据显示，在治疗R/R慢性淋巴细胞白血病(CLL)患者的1a期临床试验中，在47名可进行疗效评估的患者中，接受bexobrutideg治疗的患者的ORR达到83%，中位无进展生存期为22.1个月，中位缓解持续时间为20.1个月。值得一提的是，这些患者此前接受过多种治疗，包括共价和/或非共价BTK抑制剂。在1b期患者队列中，早期数据显示接受剂量为600 mg的bexobrutideg治疗的患者ORR为83.3%。该公司计划选用每天600 mg的剂量进行下一步开发。

Bexobrutideg在治疗接受过多种前期治疗的华氏巨球蛋白血症(Waldenström macroglobulinemia，WM)患者的1期临床试验中也表现出抗癌活性。在28名可评估疗效的WM患者中，ORR达到75%。

百济神州(BeOne Medicines)也在ASH年会上公布了其BTK降解剂BGB-16673的临床试验结果。在治疗R/R慢性淋巴细胞白血病/小淋巴细胞淋巴瘤患者的1期临床试验中，数据显示，患者的ORR达到85.3%，其中接受剂量为200 mg的BGB-16673治疗的患者亚群的ORR达到94.4%。在既往接受过共价BTK抑制剂和BCL2抑制剂治疗的患者中，ORR为93.2%。

在治疗WM患者的临床试验中，BGB-16673达到85.7%的ORR。12个月无进展生存率为78.3%。

多款分子胶降解剂临床结果公布

针对IKZF1和IKZF3这两个在多发性骨髓瘤中已经被验证的靶点，多家公司也在开发新一代分子胶降解剂。在ASH年会上，标新生物公布了在研分子胶降解剂GT919的最新临床试验结果。摘要显示，在治疗R/R多发性骨髓瘤患者的1期临床试验中，接受剂量超过2 mg GT919治疗的患者ORR达到36%，中位随访时间为5.2个月时，中位无进展生存期和缓解持续时间尚未达到。

GluBio Therapeutics公司也公布了靶向降解IKZF1和IKZF3的在研疗法GLB-002的1期临床试验结果。摘要显示，在R/R NHL患者中，GLB-002达到61.5%的ORR，观察到的最长缓解持续时间达到495天。接受2期临床试验推荐剂量GLB-002治疗的患者的ORR达到73.3%，CR为20%。

CRDMO一体化赋能蛋白降解疗法开发

作为全球医药创新的赋能者，药明康德不仅见证了靶向蛋白降解领域的快速发展，也依托其一体化、端到端的CRDMO平台，助力合作伙伴解锁靶向蛋白降解的更多可能。

在今年接受行业媒体STAT采访时，药明康德联席首席执行官杨青博士指出，在赋能全球客户的过程中，药明康德已合成了超过18.8万种复杂的靶向蛋白降解化合物，其中70多种已进入临床前候选药物阶段，10多种已进入后期开发阶段。

展望未来，药明康德将持续以一体化、端到端的CRDMO赋能平台，助力全球合作伙伴加速创新药物的研发生产进程，让科学突破更快为患者带来福祉。

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-naïve 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 Waldenström 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.