作者: Ong, Whee Sze ; Nagata, Masayoshi ; Tan, Min-Han ; Ang, Daniel ; Tay, Kae Jack ; Kanesvaran, Ravindran ; Bhagat, Ali Asgar S ; Tan, Hui Shan ; Saad, Marniza ; Wong, Siew Wei ; Ng, Quan Sing ; Chen, Kenneth ; Horie, Shigeo ; Wong, Alvin ; Chansriwong, Phichai ; Chua, Melvin L K ; Chan, Johan ; Yuen, John ; Toh, Chee Keong ; Lim, Tony ; Ng, Chi-Fai

PURPOSE:

Androgen receptor splice variant 7 (ARV-7) is a resistance mechanism to hormonal therapy in metastatic castrate-resistant prostate cancer (mCRPC). It has been associated with poor outcomes. On progression to castrate resistance, ARV-7 positivity has been identified in global populations at an incidence of 17.8%-28.8%. Here, we characterize the incidence of ARV-7 positivity in Asian patients with mCRPC in a prospective fashion and evaluate its implications on treatment outcomes.

METHODS:

Patients with mCRPC from multiple centers in Southeast and East Asia were enrolled in a prospective manner before initiation of androgen receptor signaling inhibitors or docetaxel. ARV-7 status was evaluated at baseline with three commercially available assays: AdnaTest Prostate Cancer platform, Clearbridge method, and IBN method. Clinical outcomes at progression were assessed. The primary end point of this study was prevalence of ARV-7 positivity; secondary end points were incidence of ARV-7 positivity, prostate specific antigen (PSA) response rate, PSA progression-free survival (PFS), and overall survival (OS).

RESULTS:

A total of 102 patients with a median age of 72 years at enrollment participated. Overall, an incidence of ARV-7 positivity of between 14.3% and 33.7% in Asian patients with mCRPC was demonstrated depending on the assay used. Patients found to have ARV-7 positivity at enrollment had a numerically worse PSA PFS compared with ARV-7 negative patients.

CONCLUSION:

In this study, the incidence of ARV-7 positivity in Asian patients with mCRPC was shown to be similar to the global population. Patients with ARV-7 positivity appear to have more aggressive disease with numerically worse PSA PFS and OS. Further prospective studies are needed to fully characterize the relationship that ARV-7 positivity has on prognosis of Asian patients with mCRPC.

2024-01-01·Therapeutic advances in medical oncology

A phase II study evaluating the efficacy of enzalutamide and the role of liquid biopsy for evaluation of ARv7 in mCRPC patients with measurable metastases including visceral disease (Excalibur study)

Article

作者: De Giorgi, Ugo ; Claps, Melanie ; Basso, Umberto ; Procopio, Giuseppe ; Verzoni, Elena ; Stellato, Marco ; Pircher, Chiara Carlotta ; Guadalupi, Valentina ; De Marco, Cinzia ; Sepe, Pierangela ; de Braud, Filippo ; Mennitto, Alessia ; Caffo, Orazio ; Cappelletti, Vera ; Spina, Francesco ; Santini, Daniele ; Perrucci, Bruno ; Miodini, Patrizia ; Fratino, Lucia

Background::

Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop visceral metastases, which are associated with a poor prognosis.

Objectives::

Efficacy of enzalutamide in mCRPC patients with measurable metastases, including visceral and/or extra-regional lymph nodes.

Methods::

In this phase II multicenter study, patients with mCRPC and measurable metastases received enzalutamide as the first line. Primary endpoint: 3-month (mo) disease control rate (DCR) defined as the proportion of patients with complete (CR) or partial response (PR) or stable disease (SD) as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoint: safety. Exploratory endpoint: the association between ARv7 splicing variants in basal circulating tumor cell (CTC)-enriched blood samples and treatment response/resistance using the AdnaTest ProstateCancerSelect kit and the AdnaTest ProstateCancer Panel AR-V7.

Results::

From March 2017 to January 2021, 68 patients were enrolled. One patient never started treatment. Median age: 72 years. A total of 52 patients (78%) received enzalutamide as a first line for mCRPC. The median follow-up was 32 months. At the 3-month assessment, 24 patients presented an SD, 1 patient achieved a CR, and 23 patients had a PR (3-mo-DCR of 72%). Discontinuations due to adverse events (AEs), disease-related death, or disease progression occurred in 9%, 6%, and 48% of patients. All patients reported at least one grade (G) 1–2 AE: the most common were fatigue (49%) and hypertension (33%). Six G3 AEs were reported: two hypertension, one seizure, one fatigue, one diarrhea, and one headache. Basal detection of ARv7 was significantly associated with poor treatment response (p = 0.034) and a nonsignificant association (p = 0.15) was observed between ARv7 detection and response assessments. At month 3, ARv7 was detected in 57%, 25%, and 15% of patients undergoing progressive disease, SD, and PR, respectively.

Conclusion::

The study met its primary endpoint, showing the efficacy of enzalutamide in men with mCRPC and measurable metastatic lesions in visceral and/or lymph node sites.

Trial registration::

ClinicalTrials.gov Identifier: NCT03103724. First Posted: 6 April 2017. First patient enrollment: 19 April 2017.

2021-03-01·ENDOCRINOLOGY2区 · 医学

Isoform-specific Activities of Androgen Receptor and its Splice Variants in Prostate Cancer Cells

2区 · 医学

Article

作者: Nagandla, Harika ; Robertson, Matthew J ; Coarfa, Cristian ; Putluri, Nagireddy ; Weigel, Nancy L ; Putluri, Vasanta

Abstract:

Androgen receptor (AR) signaling continues to drive castration-resistant prostate cancer (CRPC) in spite of androgen deprivation therapy (ADT). Constitutively active shorter variants of AR, lacking the ligand binding domain, are frequently expressed in CRPC and have emerged as a potential mechanism for prostate cancer to escape ADT. ARv7 and ARv567es are 2 of the most commonly detected variants of AR in clinical samples of advanced, metastatic prostate cancer. It is not clear if variants of AR merely act as weaker substitutes for AR or can mediate unique isoform-specific activities different from AR. In this study, we employed LNCaP prostate cancer cell lines with inducible expression of ARv7 or ARv567es to delineate similarities and differences in transcriptomics, metabolomics, and lipidomics resulting from the activation of AR, ARv7, or ARv567es. While the majority of target genes were similarly regulated by the action of all 3 isoforms, we found a clear difference in transcriptomic activities of AR versus the variants, and a few differences between ARv7 and ARv567es. Some of the target gene regulation by AR isoforms was similar in the VCaP background as well. Differences in downstream activities of AR isoforms were also evident from comparison of the metabolome and lipidome in an LNCaP model. Overall our study implies that shorter variants of AR are capable of mediating unique downstream activities different from AR and some of these are isoform specific.

项与 AR-V7 相关的新闻（医药）

2025-11-13

·YBCSG在线

杜益群教授点评：破 “不可成药”！PROTAC降MYC/KRAS，III期药现，未来可期||挑战泛读文献365天：第334天

[长江联盟泛读365第329天] 《Proteolysis-Targeting Chimera (PROTAC): Current Applications and Future Directions》发表在《MedComm》，该综述聚焦蛋白水解靶向嵌合体（PROTAC）技术，阐述其作为靶向蛋白降解（TPD）领域的核心平台，通过利用内源性泛素-蛋白酶体系统（UPS）实现疾病驱动蛋白的主动清除，突破传统药物“不可成药”靶点限制（如 MYC、STAT3、KRAS G12C）；目前已有超过50个PROTAC候选药物进入临床阶段，其中ARV-471（维普地司坦-vepdegestrant）已提交上市申请，ARV-110、BGB-16673等进入关键试验阶段，主要应用于肿瘤领域（如前列腺癌、乳腺癌、B细胞恶性肿瘤），同时向炎症、神经退行性疾病等拓展；文章还分析了“钩状效应”、口服生物利用度低等关键挑战，并提出分子设计优化、E3连接酶库拓展、先进递送系统（如抗体-PROTAC偶联物、纳米载体）等未来发展方向，为PROTAC的临床转化提供全面参考。主要内容一、技术核心基础 1.定义与定位 PROTAC（蛋白水解靶向嵌合体）是靶向蛋白降解（TPD）领域的核心技术平台，实现了药物研发从“传统占据式抑制”到“事件驱动式降解”的范式转变。它通过主动清除疾病驱动蛋白，为攻克传统“不可成药”靶点（如缺乏结合口袋的转录因子、突变癌蛋白等）提供了突破性路径，目前已成为精准医疗领域的重要研究方向。 2. 作用机制与分子结构作用机制：依托细胞内源性的泛素-蛋白酶体系统（UPS）发挥作用。PROTAC分子可介导目标蛋白（POI）与E3泛素连接酶形成“POI-PROTAC-E3”三元复合物，促使E3连接酶将泛素分子转移至POI的赖氨酸残基上，使POI被泛素化标记；随后，泛素化的POI会被26S蛋白酶体识别并降解。且降解完成后，PROTAC分子可从复合物中释放并循环利用，体现出催化性降解的特征。 Figure 1：PROTAC作用机制与分子结构示意图：图示清晰展示了经典PROTAC的三组分分子结构（目标蛋白结合配体+连接子+ E3泛素连接酶招募配体），并分步呈现其降解过程：1.PROTAC介导形成 “目标蛋白（POI）-PROTAC-E3 连接酶”三元复合物；2.E3连接酶将泛素（Ub）转移至POI的赖氨酸残基，完成泛素化标记；3.泛素化POI被26S蛋白酶体识别并降解为肽段；4.降解后PROTAC从复合物中释放，进入下一轮降解循环，体现催化性特征。分子结构：由三部分共价连接构成，一是POI结合配体，负责特异性识别并结合目标蛋白；二是E3连接酶招募配体，常见的有CRBN、VHL、IAP等家族配体，决定了降解过程的靶向性；三是连接子，其长度、柔韧性、极性等特性会直接影响三元复合物的空间构象，进而调控降解效率与选择性，是PROTAC分子优化的关键环节。 3. 核心优势相较于传统治疗手段，PROTAC具备三大核心优势：其一，采用“事件驱动”机制，无需持续占据靶点即可实现蛋白的彻底清除，规避了传统抑制剂对药物浓度的强依赖性；其二，具有亚化学计量活性，少量PROTAC分子即可降解大量目标蛋白，大幅降低了药物的系统暴露需求；其三，突破了“不可成药”靶点限制，即使是缺乏传统结合口袋的转录因子（如 MYC、STAT3）、突变癌蛋白（如 KRAS G12C），也可通过PROTAC技术实现靶向降解。二、与传统治疗手段的关键差异 1.小分子抑制剂以“占据式抑制”发挥作用，通过结合蛋白活性位点或变构口袋阻断其功能，但仅能作用于具有明确结合位点的“可成药”靶点（如激酶、酶类受体），难以应对“不可成药”蛋白；口服生物利用度较高，但组织穿透性有限，且易因靶点突变产生耐药性。 2.单克隆抗体同样依赖“占据式结合”，但仅能靶向胞外或细胞膜表面蛋白，无法作用于胞内靶点；无口服剂型，需通过注射给药，组织穿透性差（尤其难以进入实体瘤内部），且易引发免疫相关不良反应。 3.基因药物通过调控基因转录或翻译间接影响蛋白水平，虽可覆盖部分“不可成药” 靶点，但依赖病毒或非病毒载体递送，制备工艺复杂、成本高，且存在脱靶整合风险，起效速度较慢（需等待蛋白水平自然下降）。 4.PROTAC 采用“事件驱动式降解”，可直接清除胞内或胞外的目标蛋白，包括“不可成药”靶点；目前已有口服剂型在研（通过分子优化改善生物利用度），组织穿透性优于抗体，且因降解机制独特，对靶点突变的耐受性更强，耐药风险较低。三、代表性靶点与PROTAC分子 1.激酶靶点激酶是PROTAC研究最成熟的领域之一，依托已有的激酶抑制剂库，研发出多款高效降解剂。例如，针对EGFR突变（L858R、T790M）的 MS154、CFT8919，可选择性降解突变型EGFR，克服传统EGFR抑制剂的耐药问题；针对BTK的 BGB-16673、NX-2127，在B细胞恶性肿瘤（如慢性淋巴细胞白血病）中展现出高响应率，且能应对BTK C481S耐药突变；针对 FLT3 的 PF15、SPBS208，在急性髓系白血病模型中可有效抑制肿瘤增殖。 Figure 2：PROTAC治疗靶点及代表性降解剂分类图：以分类示意图形式呈现PROTAC技术的主要靶向蛋白类别，涵盖激酶（如EGFR、BTK、FLT3）、转录因子（如MYC、β-连环蛋白、STAT3）、激素受体（如AR、ERα）、抗凋亡/致癌蛋白（如 BCL-xL、KRAS G12D）、表观遗传调控因子（如BRD4、EZH2）、免疫炎症相关蛋白（如PD-L1、IRAK4）、代谢酶（如NAMPT、H-PGDS）、UPS 相关蛋白（如CRBN、VHL）等；每个靶点类别旁标注代表性PROTAC降解剂（如EGFR对应 MS154、CFT8919，ERα对应 ARV-471），部分还标注了核心适应症（如AR对应前列腺癌、ERα 对应乳腺癌）。 2. 转录因子靶点转录因子因缺乏结合口袋，长期被视为“不可成药”，而PROTAC技术为其靶向提供了可能。例如，针对MYC的MDEG-541，通过优化连接子构型增强三元复合物稳定性，实现MYC的胞内降解，抑制肿瘤代谢与细胞周期；针对β-连环蛋白（Wnt通路核心因子）的xStAx–VHLL，可降低结直肠癌、肝癌细胞中β-连环蛋白水平，破坏其与TCF/LEF的转录复合物；针对STAT3的SD-36、SD-2301，能解除STAT3对树突状细胞的抑制，增强T细胞免疫活性，在免疫检查点耐药肿瘤模型中展现出协同疗效。 3. 激素受体靶点激素受体相关PROTAC是临床进展最快的领域，代表药物包括针对雄激素受体（AR）的ARV-110、CC-94676，以及针对雌激素受体α（ERα）的ARV-471。其中，ARV-110可降解AR及其耐药变体AR-V7，用于治疗转移性去势抵抗性前列腺癌；ARV-471（vepdegestrant）已进入III期临床，在ESR1突变的晚期乳腺癌患者中显著延长无进展生存期，且耐受性良好。 4. 抗凋亡与致癌蛋白靶点针对抗凋亡蛋白BCL-xL的DT2216，通过降解BCL-xL避免了传统抑制剂（如navitoclax）的血小板毒性，在T细胞淋巴瘤模型中展现出安全性与有效性；针对KRAS G12D（胰腺癌、结直肠癌常见突变）的ASP3082、ASP4396，可选择性降解突变型KRAS，阻断其酶活性与支架功能，目前处于I期临床；针对SHP2（RTK通路关键因子）的SHP2-D26、ZB-S-29，能抑制ERK通路激活，与EGFR抑制剂联用可增强肺癌、乳腺癌的治疗效果。 5. 表观遗传调控因子靶点表观遗传调控因子是PROTAC的重要靶点类别，例如针对BRD4（BET 家族成员）的dBET1、ARV-825，可通过降解BRD4下调MYC表达，诱导急性髓系白血病细胞凋亡；针对EZH2（PRC2复合物核心成分）的AXT1003，虽因未披露原因终止早期临床，但为后续表观遗传相关PROTAC研发提供了经验；针对CBP/p300（组蛋白乙酰转移酶）的dCBP-1、SIAIS629048，可通过降解CBP/p300调控转录起始，在淋巴瘤模型中展现出潜力。四、临床研究进展 1. 整体临床布局目前全球已有超过50个PROTAC候选药物进入临床阶段，临床分布呈现“早期为主、逐步推进”的特征：多数候选药处于I期或I/II期（评估安全性、药代动力学与初步疗效），3款药物进入III期临床（ARV-471、BGB-16673、CC-94676），标志着PROTAC技术从实验室向临床应用的关键跨越。 2. 关键临床药物表现 ARV-471：全球首个进入III期的ERαPROTAC，在VERITAC-2试验中，针对经CDK4/6抑制剂与内分泌治疗失败的ER+/HER2-晚期乳腺癌患者，ESR1突变亚组的中位无进展生存期达5.0个月（vs安慰剂组2.1个月），且常见不良反应（疲劳、肝酶升高）多为1-2级，安全性可控。 BGB-16673：首个进入III期的BTK PROTAC，在复发/难治性B细胞恶性肿瘤中，200mg剂量组的客观缓解率达94%，且对BTK C481S耐药突变仍有效，在套细胞淋巴瘤、滤泡淋巴瘤等亚型中展现出广谱活性。 CC-94676：AR靶向PROTAC，用于治疗转移性去势抵抗性前列腺癌，在rechARge III期试验中以影像学无进展生存期为主要终点，目前处于招募阶段，有望解决AR抑制剂耐药问题。 3. 临床应用拓展除肿瘤领域外，PROTAC开始向非肿瘤疾病拓展：例如针对IRAK4（炎症通路关键因子）的KT-474，在特应性皮炎、化脓性汗腺炎患者中实现≥95%的IRAK4降解，显著改善皮肤炎症标志物；针对STAT6的KT-621，作为全球首个STAT6 PROTAC，在健康受试者中展现出快速降解活性，目前用于特应性皮炎的I期临床正在推进。五、技术挑战与未来方向 1. 当前核心挑战口服生物利用度低：PROTAC分子量大（多超过800Da）、极性高、氢键供体/受体多，导致肠道吸收差，例如ARV-110在大鼠中的口服生物利用度仅23.8%，需通过高剂量给药（如420mg/天）维持疗效，增加患者负担与“钩状效应” 风险。 “钩状效应”：高浓度下PROTAC易形成POI-PROTC或PROTAC-E3二元复合物，反而抑制三元复合物形成，降低降解效率，给剂量优化带来困难。安全性风险：部分PROTAC因脱靶降解或影响必需蛋白（如心肌细胞蛋白）引发毒性，例如BRD9 PROTAC FHD-609因导致4级QT间期延长被部分暂停临床；此外，E3连接酶（如CRBN）的泛底物效应可能引发非预期不良反应。递送效率不足：对于中枢神经系统疾病（如神经退行性疾病），PROTAC难以穿透血脑屏障；对于实体瘤，组织穿透性差导致肿瘤内部药物浓度不足。 2. 未来发展策略分子设计优化：通过缩短连接子长度、增加刚性，降低分子柔性以改善渗透性；开发新型E3连接酶配体（如ZFP91、DCAF家族配体），拓展E3连接酶库，提升组织特异性与降解选择性；利用AI辅助设计预测三元复合物稳定性，优化POI与E3配体的结合亲和力比例，减轻“钩状效应”。先进递送系统：研发抗体-PROTAC偶联物（AOCs）、适配体-PROTAC偶联物（APCs），依托抗体/适配体的靶向性实现精准递送；利用脂质纳米颗粒（LNPs）、聚合物纳米载体、外泌体等封装PROTAC，保护分子免受酶解，增强组织穿透性（如LNPs介导的PROTAC可穿透血脑屏障）；借鉴GT20029（外用AR PROTAC）的经验，开发局部给药剂型（如吸入剂、局部凝胶），降低全身毒性。 Figure 3：PROTAC 先进递送系统示意图：图示展示了当前用于改善PROTAC递送效率的主流载体技术，包括：1.生物靶向载体（抗体、适配体），通过特异性结合细胞表面抗原/受体介导PROTAC胞内递送（如抗体-PROTAC偶联物AOCs）；2.纳米载体（脂质纳米颗粒LNPs、聚合物纳米颗粒、无机纳米颗粒如金纳米颗粒、外泌体），通过封装PROTAC保护其免受酶解，同时利用EPR效应（实体瘤高通透性和滞留效应）增强肿瘤靶向性；3.局部递送相关载体（如用于皮肤疾病的凝胶载体、用于肺部疾病的吸入式载体）；图中还标注了各递送系统的核心优势（如LNPs提升血脑屏障穿透性、外泌体降低免疫原性）。适应症拓展与联合治疗：向神经退行性疾病（如降解tau蛋白、α-突触核蛋白）、代谢疾病（如降解SREBP、HMGCR）、自身免疫疾病（如降解NF-κB、IRAK4）拓展；探索PROTAC与化疗、免疫检查点抑制剂、放疗的联合策略，例如BCL-xL PROTAC与PD-1抑制剂联用可增强抗肿瘤免疫，BRD4 PROTAC与PARP抑制剂联用可协同抑制DNA修复。临床转化支撑：建立PROTAC特异性的安全性评估模型（如心肌细胞类器官、AI毒性预测模型）；开发降解效率定量检测方法与疗效预测生物标志物（如E3连接酶表达水平、POI磷酸化状态）；推动监管体系完善，明确PROTAC的药代动力学、毒理学评价标准。六、总结与展望 PROTAC技术自2001年概念提出以来，已从实验室工具快速发展为临床阶段的革命性疗法，其核心价值在于突破“不可成药”靶点限制，为传统疗法耐药的疾病（如突变型肿瘤、难治性自身免疫病）提供了新选择。尽管当前面临口服生物利用度、递送效率、安全性等挑战，但随着分子设计优化、递送技术创新与临床经验积累，PROTAC 有望在未来10年成为精准医疗的核心平台之一。 Figure 4：PROTAC技术未来发展方向框架图：以框架图形式梳理PROTAC技术的核心发展方向，涵盖六大维度：1.分子设计优化（如三元复合物稳定性提升、口服生物利用度改善、“钩状效应”缓解）；2. E3连接酶库拓展（如新型E3配体开发、组织特异性E3应用）；3.器官特异性靶向（如血脑屏障穿透型PROTAC、肝肾靶向PROTAC、肺部吸入式PROTAC）；4.先进递送系统（如纳米载体、AOCs、prodrug策略）；5.适应症拓展（如从肿瘤向神经退行性疾病、代谢疾病、自身免疫疾病延伸）；6.临床转化支撑（如生物标志物开发、安全性评估模型建立、监管体系完善）；各维度间通过箭头标注关联关系（如“E3连接酶拓展”可推动 “器官特异性靶向”）。未来，PROTAC技术将朝着“更精准、更安全、更广泛”的方向发展：一方面，通过组织特异性E3连接酶的应用与智能递送系统的开发，实现“精准降解、低毒高效”；另一方面，通过与AI、纳米技术、免疫疗法的融合，拓展至神经、代谢、炎症等更多疾病领域，最终为患者提供更优质的治疗方案，推动药物研发进入“蛋白降解”的新时代。推荐理由 “破不可成药”壁垒：突破传统药物无法靶向无结合口袋蛋白的局限，对MYC、KRAS G12C等 “不可成药” 靶点实现精准降解，拓展治疗边界。催化式长效作用：亚化学计量活性特性下，单分子可循环降解多靶点蛋白，无需持续高浓度给药，降低系统暴露与耐药风险。跨疾病场景适配：从肿瘤（如AR/ERα 相关癌症）向炎症（IRAK4降解）、神经退行性疾病（tau 蛋白降解）延伸，应用场景多元。克服传统耐药：通过彻底清除靶点蛋白（而非仅抑制功能），应对靶点突变（如BTK C481S、EGFR T790M）引发的传统药物耐药问题。参考文献：Fan, G., Chen, S. L., Zhang, Q. P., Yu, N., Shen, Z. Y., Liu, Z. J., Guo, W. M., Tang, Z. H., Yang, J., & Liu, M. (2025). Proteolysis-Targeting Chimera (PROTAC): Current Applications and Future Directions. MedComm, 6(e70401). https://doi.org/10.1002/mco2.70401 点评专家杜益群教授复旦大学附属肿瘤医院首先，文章对PROTACs与传统小分子抑制剂、单克隆抗体等药理模式进行了系统的对比分析，有力地突出了PROTACs在驱动机制、亚化学计量活性以及解决“不可成药”靶点（如MYC、STAT3等转录因子）等方面的独特优势。这种机制上的颠覆性，是PROTAC革命的核心所在。其次，综述对PROTACs临床进展的覆盖尤其及时和全面，其降解靶点涉及激酶靶点、转录因子、激素受体、免疫和炎症靶点等等诸多靶标。它敏锐地捕捉到了PROTACs发展中最重要的里程碑：雌激素受体α降解剂vepdegestrant (ARV-471)和BTK降解剂BGB-16673等分子成功进入关键III期临床试验，并重点提到了vepdegestrant提交新药申请（NDA）的重大进展。这标志着PROTAC技术正从概念验证走向商业化现实。此外，文章专门辟出章节讨论递送系统和E3连接酶工具的扩展，凸显了对核心技术瓶颈的深刻理解。特别是对纳米载体、抗体-PROTAC偶联物（AOCs）以及利用CD36介导内吞途径来解决大分子PROTAC细胞渗透性问题的讨论，提供了富有创新性的解决方案。作为点评，我们必须指出综述中强调的几个关键挑战，这些挑战将决定PROTAC技术的未来。生物利用度与成药性：PROTACs分子量大、极性高，导致口服生物利用度低（如ARV-110的低口服吸收率）。这不仅限制了其在某些适应症（如中枢神经系统疾病）中的应用，也增加了剂量要求，并带来了“钩效应”（Hook Effect）的风险—即浓度过高反而降低药效。使剂量优化策略更加复杂。临床安全性与脱靶效应：综述援引了BRD9降解剂（CFT-8634、FHD-609）因临床疗效不足或心脏毒性而终止开发的案例，这敲响了警钟。虽然PROTACs旨在靶向降解，但其E3连接酶招募策略仍可能引发脱靶效应或降解关键的心肌蛋白，安全性仍是临床转化中最严峻的考验。总而言之这篇综述不仅是对现有成就的总结，更是一份面向未来的技术路线图。它将靶点选择、分子优化、先进递送系统和临床转化策略融为一体，为加速PROTAC技术走向更广泛的非肿瘤适应症（如炎症、神经退行性疾病和衰老）提供了坚实的理论基础和实践方向。编辑：XU、LYY 审核：张剑、李恒宇文献传递：如需全文请后台留言您的邮箱。记得点赞在看留言打卡噢~

蛋白降解靶向嵌合体临床结果

2025-09-26

·GlobeNewswire-Health Care

Akari Therapeutics’ Preclinical Data Demonstrates the Potential of its Novel ADC Spliceosome Modulating Payload, PH1

Data highlights ability of Akari’s ADC payload, PH1, to suppress the levels of the AR-V7 receptor that is responsible for driving hormone refractory prostate cancer progression No current therapies have proven to be effective in AR-V7 driven tumors Sept. 24, 2025 -- Akari Therapeutics, Plc (Nasdaq: AKTX), an oncology biotechnology company developing novel payload antibody drug conjugates (ADCs), today announced key preclinical data demonstrating the potential of its novel antibody drug conjugate (ADC) spliceosome modulating payload, PH1, for the treatment of tumors fueled by alternative splicing-drivers, such as the Androgen Receptor splice variant 7 (AR-V7) in prostate cancer. AR-V7 is a key driver for progression of metastatic castration resistant prostate cancer (mCRPC). During progression of hormone-sensitive prostate cancer, many patients fail to respond to current first-line therapies known as Androgen Receptor Pathway Inhibitors (ARPIs), which include enzalutamide (Xtandi, $6B/annual sales), apalutamide (Erleada, $3B/annual sales) and darolutamide (Nubeqa, $1.6B/annual sales). Importantly, as patients lose ARPI response, their tumors transform and significantly increase in AR-V7 expression. As a result, there is an increasing and significant unmet need for targeted therapy options in ARPI-resistant hormone refractory patients, where there are currently limited options such as traditional chemotherapy like taxanes. As referenced in the Company’s recent patent filing, preclinical data demonstrated that Akari’s ADC payloadPH1 is able to suppress the expression levels of the AR-V7 receptor in a hormone-refractory mCRPC model called 22Rv1. As a control, ARPIs had no effect on AR-V7 receptor expression in these experiments, which was expected given the refractory nature of these prostate cancer cell lines. Surprisingly, in a different model, of hormone-sensitive LnCAP cells that express high levels of normal Androgen Receptor (i.e. ARPI sensitive) and lack AR-V7, PH1 demonstrated a benefit as a single agent, and additive effect when combined with either Xtandi or Erleada. The Company believes this combined efficacy data may potentially lead to the development of robust first-line combination regimens of Xtandi or Erleada with a PH1 payload conjugated ADC (PH1 ADC) to target prostate cancer that is sensitive to ARPIs. As progression is often linked to AR-V7 expression, and PH1 reduces AR-V7 expression, it is hypothesized that the combination of ARPI plus PH1 ADCs may slow the development of resistance and AR-V7-driven tumor progression which typically occurs after patients progress on Xtandi or Erleada. Akari has plans to test this hypothesis using PH1 ADCs against different prostate cancer targets in future research. Abizer Gaslightwala, President and Chief Executive Officer of Akari Therapeutics commented, “We believe these compelling preclinical data support the rationale for Akari to develop a novel ADC with our PH1 spliceosome-modulating payload targeting prostate cancer either alone or in partnership with potential partners. Our goal is to develop the first ADC therapeutic in prostate cancer, either as a first-line combination therapy with ARPIs or a second-line therapy post ARPI failures in tumors driven by AR-V7. We are excited to continue to advance this novel spliceosome modulating payload to drive robust anti-cancer biological mechanisms to treat difficult alternative splicing-driven tumors, for which there are currently no effective treatment options today.” The Company plans to present the preclinical data at an upcoming scientific conference. Akari Therapeutics is an oncology biotechnology company developing next-generation spliceosome payload antibody drug conjugates (ADCs). Utilizing its innovative ADC discovery platform, the Company has the ability to generate ADC candidates and optimize them based on the desired application to any target of interest. Akari’s lead candidate, AKTX-101, targets the Trop2 receptor on cancer cells and with a proprietary linker, delivers its novel PH1 payload directly into the tumor. Unlike current ADCs that use tubulin inhibitors and DNA damaging agents as their payloads, PH1 is a novel payload that is a spliceosome modulator designed to disrupt RNA splicing within cancer cells. This splicing modulation has been shown in preclinical animal models to induce cancer cell death while activating immune cells to drive robust and durable activity. In preclinical studies, AKTX-101 has shown to have significant activity and prolonged survival, relative to ADCs with traditional payloads. Additionally, AKTX-101 has the potential to be synergistic with checkpoint inhibitors and has demonstrated prolonged survival as both a single agent and in combination with checkpoint inhibitors, as compared to appropriate controls. The Company is generating validating data on its novel payload PH1 to continue advancing its lead asset, as well as other undisclosed targets with this novel payload. The content above comes from the network. if any infringement, please contact us to modify.

抗体药物偶联物

2025-04-23

·Endpoints

Exclusive: Chicago startup Grove Biopharma nabs $30M Series A

A small Northwestern University spinout attempting to develop a twist on biologics has pulled together a $30 million Series A. The startup, named Grove Biopharma, weathered the pandemic and, after more than a year of fundraising, pushed through the difficult financing environment in a bid to prove its platform can hit intracellular disease targets and potentially open up a new field of medicines. To get to this point, Grove had to rightsize its original ambition of raising a $50 million Series A, CEO Geoffrey Duyk said in an interview. The funding environment has been particularly difficult for startups like Grove that are attempting to create new platforms. Risk-averse investors have mostly concentrated their bets on clinical-stage assets or pipelines on the cusp of human trials. Duyk has seen both sides of the coin, having worked in R&D at Millennium and Exelixis in the 1990s and early 2000s before spending two decades on the investing side. “This is obviously the most challenging environment I’ve seen in my entire career,” Duyk said, “and I’ve been through many, many cycles.” The Series A, albeit smaller than planned, does come with industry validation via Eli Lilly, which took part in the DCVC Bio-led round. Grove previously raised about $8 million in seed funding, Duyk said. The nimble startup, which has about a dozen employees, is also part of the burgeoning Chicago biotech scene . Grove was incubated by local investor Portal Innovations, and it is housed in the same West Loop building as the Chan Zuckerberg Biohub Chicago. The startup’s platform seeks to make synthetic biomolecules that can go after intracellular targets. Whereas the industry has traditionally thought of materials as delivery mechanisms, Grove wants to flip the switch on that thinking. “It’s not just new drugs. It’s not just a new molecule. It’s a new way to develop drugs,” scientific founder and Northwestern professor Nathan Gianneschi said in an interview. “This is turning that around and saying, ‘Well, no, the material itself is the drug.'” Gianneschi and Duyk co-founded Grove in 2020 alongside chief technology officer Paul Bertin. Duyk called it a “three-men-in-a-garage” type of startup after it spun out from the university lab. “Nathan was asking some interesting questions: What if you rethought what a protein was? Instead of a protein being a linear polymer of amino acids, what if you made it a branch of polymer peptides?” Duyk said. Grove’s molecules look like little trees, hence the company’s name, according to Gianneschi. He and his team discovered a fully synthetic molecule that incorporated the critical features of an antibody but could also get inside a cell, Duyk said. “It was like a little bit of a dream to begin with, that you could mimic proteins using polymer chemistry,” Gianneschi said. Its first clinical attempt will be in prostate cancer with a molecule that goes after AR-V7, an androgen receptor splice variant. That said, the startup will likely need more financing to get into the first human trial, Duyk said. Grove’s other oncology programs include work in SHOC2, the MYC/WDR5 interaction, and the MYC transactivation domain. Its in-house R&D engine is also exploring neurodegenerative diseases by way of tau pathology and the Keap1-Nrf2 pathway. Grove is hopeful that its platform can lead to medicines that are delivered via IV, under-the-skin injections or even topicals, Duyk said. Work has yet to be done to see if they can be made available orally, he added. The company also plans to seek biopharma partnerships, saying its platform can be applied in multiple areas, including degraders. “We can use our molecules to do the equivalent of ADCs,” Duyk said. “We can use our molecules to do the equivalent of radiopharmaceuticals, so there’s a lot of interest in pursuing that.” Editor’s note: This story was updated to correct the AR-V7 program is in prostate cancer, not pancreatic.

100 项与 AR-V7 相关的药物交易

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