Patidegib

**报告日期**: 2026年7月3日**靶点概况**: uPARAP是一个新型胶原蛋白内吞受体，目前仅Adcendo ApS一家公司在临床阶段推进该靶点的ADC药物开发，属于全球独家靶点赛道。目录 1. [靶点生物学概述](#1-靶点生物学概述) 2. [靶点表达谱与治疗窗口分析](#2-靶点表达谱与治疗窗口分析) 3. [药物研发管线全景](#3-药物研发管线全景) 4. [核心药物 ADCE-D01 深度解析](#4-核心药物-adce-d01-深度解析) 5. [临床前研究关键数据](#5-临床前研究关键数据) 6. [Adcendo 公司分析](#6-adcendo-公司分析) 7. [竞争格局与专利态势](#7-竞争格局与专利态势) 8. [uPARAP在胰腺癌中的作用深度分析](#8-uPARAP在胰腺癌中的作用深度分析) 9. [靶点拓展潜力](#9-靶点拓展潜力) 10. [风险评估](#10-风险评估) 11. [总结与展望](#11-总结与展望)1. 靶点生物学概述1.1 基本信息属性详情**基因名***MRC2*（Mannose Receptor C-type 2）**蛋白别名**uPARAP、Endo180、CD280、TEM9**蛋白家族**甘露糖受体家族（Mannose Receptor Family）**功能分类**Ⅰ型跨膜内吞受体**核心配体**胶原蛋白片段（Collagen fragments）、凝集素（Collectins）**细胞分布**间充质来源细胞（成纤维细胞、成骨细胞、软骨细胞）**结构域组成**富半胱氨酸结构域（Cys-rich）→ 纤连蛋白Ⅱ型结构域（FNII）→ 8个C型凝集素样结构域（CTLD1-8）→ 跨膜区 → 胞内尾1.2 核心生物学功能 uPARAP是**胶原蛋白内吞周转的主调控因子**，其核心功能流程如下：**胶原降解通路**：1. 细胞外胶原纤维被MMPs切割为小片段2. 胶原片段与细胞表面uPARAP结合3. 通过网格蛋白包被小窝（clathrin-coated pits）快速内吞4. 运送至早期内体5. **uPARAP受体循环回细胞膜**（持续再利用）6. 胶原被运送至溶酶体被组织蛋白酶降解1.3 ADC开发的靶点优势 uPARAP具备**多项理想ADC靶点特征**，这在其发现之初即被学术界关注：ADC靶点理想特征uPARAP表现评价**肿瘤选择性高表达**肉瘤、GBM等间充质肿瘤显著过表达✅**正常组织表达受限**仅活化成纤维细胞、骨衬细胞等少数部位✅**高效内吞**结合后5-10分钟内快速内化，每小时循环数次✅⭐**直接溶酶体递送**clathrin介导→早期内体→溶酶体直接路由✅⭐**组成型内吞（无需抗体诱导）**配体非依赖性持续内化✅⭐（罕见）**基因敲除表型温和***Mrc2* KO小鼠无明显表型异常✅**可成药性**已验证多种抗体可高效结合并内化✅**关键差异化优势**：uPARAP的"组成型快速内吞+直接溶酶体递送"属性在现有临床阶段ADC靶点中极为罕见，这意味着payload递送效率可能远超依赖抗体交联诱导内吞的传统靶点 [1][2]。1.4 非胶原相关功能 除胶原内吞外，uPARAP还被发现参与：**VEGFR-2/VEGFR-3异源二聚化调控**：影响淋巴管生成 [3]**固有免疫**：结合并内化凝集素（collectins），参与病原体清除**细胞迁移**：通过调控细胞外基质重塑影响肿瘤侵袭**骨发育**：成骨细胞和骨细胞的胶原代谢2. 靶点表达谱与治疗窗口分析2.1 肿瘤组织表达A. 肿瘤细胞直接表达（Tumor Cell Expression）肿瘤类型uPARAP表达状态数据来源**软组织肉瘤（STS）**强过表达Adcendo/IHC**骨肉瘤**强过表达Adcendo/文献**胃肠道间质瘤（GIST）**强过表达Adcendo**间皮瘤**强过表达Adcendo**胶质母细胞瘤（GBM）**强过表达文献 [1]**急性髓系白血病（AML）亚型**部分阳性文献 [1]B. STS亚型IHC详细表达率（组织芯片）肉瘤亚型Endo180阳性率样本量去分化脂肪肉瘤**93.1%**54/58纤维肉瘤**87.5%**21/24滑膜肉瘤**76.1%**32/42平滑肌肉瘤**64.2%**97/151未分化多形性肉瘤（UPS）**64.3%**65/101横纹肌肉瘤**64.0%**126/197高分化脂肪肉瘤**38.5%**20/52**总体****66.4%**415/625来源：ICR/AACR MCT 2023 [4]。A5/158单抗IHC染色，染色模式为胞浆+核周（内体聚集特征）。C. 基质表达（Stromal Expression）肿瘤类型基质uPARAP表达表达细胞乳腺癌CAFs中上调肿瘤相关成纤维细胞结肠癌CAFs中上调肿瘤相关成纤维细胞胰腺癌CAFs中上调肿瘤相关成纤维细胞前列腺癌CAFs中上调肿瘤相关成纤维细胞头颈癌CAFs中上调肿瘤相关成纤维细胞2.2 正常组织表达组织/细胞类型表达水平备注静息成纤维细胞低/无大部分正常组织活化成纤维细胞/肌成纤维细胞中等伤口愈合、组织重塑成骨细胞/骨细胞阳性骨发育和重塑相关循环白细胞**阴性**重要的安全性特征肝、肾、心、肺等实质器官低/无限制性表达2.3 治疗窗口评估维度评估**肿瘤/正常组织表达比**多数肉瘤亚型显著高于正常组织**受体拷贝数**肿瘤细胞 10,000-100,000 copies/cell**正常组织安全性**KO小鼠无明显表型 → 靶向安全性预期良好**临床前毒性**小鼠模型中未观察到明显体重下降或组织病理学异常**骨组织潜在风险**骨衬细胞表达uPARAP，但临床前模型中骨结构保持完整3. 药物研发管线全景3.1 管线概览药物编号靶点类型适应症临床阶段状态**ADCE-D01**uPARAP（MRC2）ADC（Topo I抑制剂）软组织肉瘤Phase I/II招募中ADCE-T02Tissue Factor（TF）ADC（Topo I抑制剂）实体瘤（HNSCC、PDAC等）Phase I 扩展队列招募中ADCE-B05未披露新型靶点ADC鳞状细胞肿瘤Phase I首例给药**结论**: **uPARAP靶点目前仅有ADCE-D01一款药物进入临床阶段，且Adcendo是该靶点的全球独家开发者**。这是一个典型的"孤品靶点"格局。3.2 ⚠️ 关键概念辨析：uPARAP ≠ uPAR —— BL-M24D1靶点澄清**重要提示**：近期部分数据库（如药渡Pharmacodia）在BL-M24D1的靶点字段中列出了"uPARAP/Endo180/MRC2/CD280"等别名，但经**原始临床试验注册数据交叉验证**（ChiCTR2500112345），BL-M24D1的真实靶点为**uPAR（CD87，PLAUR基因）**，而非uPARAP（Endo180/MRC2/CD280）。uPAR vs uPARAP 对比属性**uPAR****uPARAP（Endo180）****全称**Urokinase Plasminogen Activator ReceptoruPAR-Associated Protein**基因***PLAUR**MRC2***CD编号**CD87CD280**蛋白家族**Ly-6/uPAR超家族（GPI锚定）甘露糖受体家族（Ⅰ型跨膜蛋白）**核心配体**uPA（尿激酶型纤溶酶原激活物）胶原蛋白片段**功能**纤溶酶原激活、细胞迁移/粘附、信号转导胶原内吞降解、基质重塑**肿瘤表达**多种实体瘤（NSCLC、结直肠癌、乳腺癌等）间充质肿瘤（肉瘤、GBM）+ CAFs**临床在研ADC****BL-M24D1（百利天恒）****ADCE-D01（Adcendo）**BL-M24D1 基本信息项目详情**药物名称**BL-M24D1（注射用BL-M24D1）**开发商**四川百利天恒药业 / 百利多特生物**药物类型**ADC（新一代毒素平台，与BL-B16D1共享linker+毒素）**靶点****uPAR（CD87/PLAUR）** ❗非 uPARAP**临床阶段**Phase I（Ia剂量递增 + Ib扩展）**适应症**复发/难治性多发性骨髓瘤、血液肿瘤、胃肠道肿瘤、HNSCC、NSCLC及其他实体瘤**主要试验**NCT07255898（血液肿瘤，华西医院）；NCT07279428（胃肠道肿瘤）；NCT07232524（HNSCC）**IND批准**2025年10月NMPA批准**试验招募**约33人（Ia）+ 30人（Ib），仅在中国进行**结论**：BL-M24D1是uPAR靶向ADC，与ADCE-D01（uPARAP靶向）属于**不同靶点、不同赛道**。由于命名相似（uPAR vs uPARAP），两者在数据库中容易被混淆，但在靶点生物学、适应症策略和竞争格局上**完全不重叠**。当前全球范围内，uPARAP靶点的临床阶段药物**仍然仅有ADCE-D01一款**。3.3 临床前/学术阶段候选分子分子/项目研发方类型关键发现时间**2h9-vc-MMAE**哥本哈根大学ADC（MMAE）系统性给药100%完全治愈U937 AML模型2017**A5/158-vc-MMAE**ICR伦敦ADC（MMAE）肉瘤模型原发灶消退+转移显著减少2023**抗FNII中和抗体**学术团队裸抗骨肉瘤模型中显示抗肿瘤效果2022这些学术分子的发现为Adcendo的ADCE-D01开发奠定了靶点验证基础，但尚未独立进入临床开发。4. 核心药物 ADCE-D01 深度解析4.1 药物结构 ADCE-D01 = AB-004（人源化抗uPARAP单抗） + 四肽蛋白酶可切割连接子 + P1021（Topo I抑制剂）组件详情**抗体**AB-004 — 人源化抗人uPARAP单克隆抗体**连接子**四肽蛋白酶可切割连接子（protease cleavage tetra-peptide linker）**载荷**P1021 — Topoisomerase I抑制剂**作用机制**抗体结合uPARAP → 快速内吞 → 溶酶体中连接子被组织蛋白酶切割 → P1021释放 → DNA损伤 → 肿瘤细胞凋亡**药物分类**First-in-Class ADC4.2 临床开发时间线时间节点里程碑事件2023年Adcendo完成~$89.6M A轮融资，与Duality Biologics达成授权协议2024年10月FDA批准ADCE-D01 IND申请，可启动Phase I/II研究2024年11月Adcendo完成$135M超额认购B轮融资**2025年6月5日****ADCElerate1试验正式启动，首例患者给药** [5]**2025年10月****FDA授予Fast Track认定（软组织肉瘤）** [6]2026年1月ClinicalTrials.gov记录更新（NCT06797999）**2026年4月****FDA授予孤儿药资格认定（ODD）** [7]2026年4月Adcendo完成$75M C轮融资4.3 ADCElerate1 临床试验设计（NCT06797999）参数详情**试验名称**ADCElerate1**试验分期**Phase I/II**试验设计**多中心、开放标签、剂量递增+扩展**适应症**转移性和/或不可切除的软组织肉瘤（STS）**给药方案**ADCE-D01单药，静脉输注**主要终点**MTD/MAD、RP2D确定；DLT发生率；安全性/耐受性（TEAEs）**次要终点**ORR、DOR、PFS、CBR、TTR（RECIST v1.1）；PK参数（Cmax、Tmax、AUC）**关键入组标准**≥18岁；组织学确认的STS；1-2线系统治疗后进展；ECOG 0-1；预期寿命≥3月**排除标准**活动性脑转移；未控制CVD；4周内接受过系统抗癌治疗**预计入组人数**未公开**试验地点**8个中心（美国5个：科罗拉多大学、迈阿密大学、MSKCC、MD Anderson等 + 欧洲3个：比利时UZ Leuven、法国Centre Léon Bérard、德国Essen + 英国Royal Marsden）**开始日期**2025年6月5日（实际）**预计完成**2029年2月27日4.4 关键研究者网络研究者机构专长领域Robert Maki, MDMSKCC肉瘤内科Patrick Schöffski, MDUZ Leuven肉瘤新药开发Jean-Yves Blay, Prof.Centre Léon Bérard肉瘤综合治疗Sebastian Bauer, MDUniversitätsklinikum Essen肉瘤/GISTRobin Jones, MDRoyal Marsden肉瘤临床研究Breelyn Wilky, MDUniversity of Colorado肉瘤免疫治疗ADCE-D01已汇聚**全球顶级肉瘤临床中心**，研究者阵容强大。4.5 监管推进认定授予时间核心权益**FDA Fast Track**2025年10月加速审批路径、FDA频繁沟通、滚动审评资格**FDA Orphan Drug（ODD）**2026年4月7年美国市场独占权、临床试验税收抵免、FDA申请费减免5. 临床前研究关键数据5.1 2h9-vc-MMAE（哥本哈根大学，2017）[1]体外数据细胞系肿瘤类型uPARAP状态ADC敏感性U937AML阳性**高敏**NB-4APL阳性**高敏**THP-1单核细胞白血病阳性敏感HT1080纤维肉瘤阳性敏感GCT纤维组织细胞瘤阳性敏感RD横纹肌肉瘤阳性敏感KNS42GBM阳性敏感HS683GBM阳性敏感U373 MGGBM阳性敏感U937 KOAML（CRISPR KO）**阴性****不敏感**HEK293非恶性极低**不敏感** **特异性验证实验**：未修饰2h9抗体预处理可**完全挽救**细胞免受ADC杀伤uPARAP表面清除预处理使毒性**降低~10倍**溶酶体半胱氨酸蛋白酶抑制剂E-64D**完全消除**ADC活性 **细胞周期效应**：U937、NB-4表现为凋亡增加（sub-G1↑）；GCT表现为G2/M阻滞；多数实体瘤细胞系为混合效应。体内数据给药方案剂量结果皮下局部（q4d×4）3 mg/kg**9/10小鼠肿瘤消失**；5/10完全治愈（3月无复发）尾静脉系统（q4d×3）5 mg/kg**10/10（100%）完全治愈**（3月零复发）皮下局部升高剂量（q4d×3）5 mg/kg**100%完全治愈** **安全性**：全部治疗组**零体重下降**肝脏H&E染色无异常uPARAP阳性骨衬细胞在治疗中保持完整5.2 A5/158-vc-MMAE（ICR伦敦，2023）[4]体外数据参数数值内吞速度**>50%在2分钟内内化**溶酶体共定位30分钟内确认（LysoTracker）IC50（Endo180+细胞）~5 μg/mL（相对较高，提示需优化）Endo180-细胞相对耐药DAR4.0体内数据（MG-63骨肉瘤异种移植，NSG小鼠）指标结果**原发肿瘤**显著消退；剂量依赖性（2.5→5→10 mg/kg）；**10 mg/kg几乎完全消退****肺转移（生物发光）****显著减少****肝转移发生率**对照组73%（8/11）→ **治疗组0%（0/5）****淋巴结转移发生率**对照组82%（9/11）→ **治疗组20%（1/5）****延迟治疗**即使肿瘤达8.5mm才开始治疗仍有效**未结合A5/158裸抗**无抗肿瘤效果（支持ADC机制依赖性）**Isotype-vc-MMAE对照**无效果5.3 ADCE-D01自身临床前数据 Adcendo公布的ADCE-D01临床前亮点：**多个靶适应症体内概念验证**（pan-sarcoma覆盖范围）**多种payload MoA验证**（可能评估过MMAE、Topo I抑制剂等多种载荷）**最终选择Topo I抑制剂P1021**而非MMAE，可能出于疗效/毒性平衡优化6. Adcendo 公司分析6.1 公司概况项目详情**全称**Adcendo ApS**总部**丹麦哥本哈根**运营中心**波士顿，马萨诸塞州**发展阶段**临床阶段**CEO**Michael Pehl（前Bayer/Schering肿瘤学高管）**CMO**Dr. Lone Ottesen, MD, PhD**全球法规负责人**Dr. Victoria Marsh**创始人/核心科学**基于哥本哈根大学uPARAP研究平台**网站**https://adcendo.com6.2 融资历程轮次时间金额领投方关键参投方A轮2023年~$89.6M未公开RA Capital、Novo Holdings、Pontifax、HealthCap、Gilde、Ysios CapitalB轮2024年11月**$135M**（超额认购）**TCGX**TPG、Orbimed、Venrock、Surveyor Capital（Citadel）、Logos Capital + 全部现有股东C轮2026年4月**$75M****Jeito Capital**Vida Ventures、BPI France、EIFO + 全部现有股东**累计**—**~$300M**——6.3 关键技术合作合作方合作内容时间**Duality Biologics（映恩生物）**ADC技术平台授权（linker-payload）2023**MSD（默沙东）**ADCE-T02 + KEYTRUDA®联合用药临床合作2026年5月注：与Duality Biologics（中国ADC公司）的合作可能为ADCE-D01的linker-payload技术来源，值得关注映恩生物的平台技术对uPARAP ADC的贡献。6.4 董事会构成（B轮后）成员背景John Haurum（主席）生物技术连续创业者Cariad ChesterTCGX Managing PartnerNandita ShangariRA Capital Managing DirectorJeroen BakkerNovo Holdings PartnerCarolyn NgTPG Life Sciences InnovationsOhad HammerPontifax Venture Capital PartnerIyona RajkomarDawnBio/KKE Managing PartnerMichael PehlAdcendo CEO投资方阵容为**全球顶级生命科学VC syndicate**，包括TCGX、Orbimed、RA Capital、Novo Holdings等一线机构。7. 竞争格局与专利态势7.1 竞争格局层面分析**靶点层面**uPARAP为Adcendo**全球独家**临床靶点，无其他公司在临床阶段竞争**适应症层面**软组织肉瘤领域ADC竞争者包括MAGEC2靶向ADC等，但靶点不同**学术竞争**哥本哈根大学、ICR伦敦等学术团队掌握早期抗体（2h9、A5/158），但未进入商业化开发**间接竞争**其他"肉瘤ADC"开发公司（如靶向LRRC15、B7-H3的ADC）7.2 专利与知识产权方面评估**核心抗体专利**Adcendo持有AB-004及其人源化版本的专利组合**linker-payload来源**从Duality Biologics（映恩生物）授权，非自研**靶点专利**uPARAP作为靶点的概念验证由哥本哈根大学完成，基础专利存在，但ADC应用由Adcendo独有**竞争壁垒**抗体IP + 临床数据包 + 监管认定（Fast Track + ODD）形成三年层壁垒7.3 靶点壁垒评估：⭐⭐⭐⭐⭐（极高）**独家临床资产**：全球仅1款临床阶段药物**学术→产业转化完成**：哥本哈根大学已验证靶点，Adcendo完成产业转化**时间窗口**：后发者需重复靶点验证→抗体发现→临床前→IND（至少5年）**监管护城河**：ODD 7年市场独占 + Fast Track加速路径8. uPARAP在胰腺癌中的作用深度分析8.1 胰腺导管腺癌（PDAC）病理背景 胰腺癌中约90%为胰腺导管腺癌（PDAC），其最突出的病理特征之一是**重度促结缔组织增生性间质反应（desmoplastic stroma）**——肿瘤组织中基质成分可占肿瘤体积的**50%-80%**，远超多数其他实体瘤。该间质的主要细胞成分为：细胞类型来源功能**胰腺星状细胞（PSC）活化后的CAFs**静息PSC→活化肌成纤维细胞胶原大量分泌、基质重塑**肿瘤相关成纤维细胞（CAFs）**多种来源（PSC、骨髓前体等）ECM沉积、免疫抑制微环境免疫细胞（TAM、MDSC、Treg）骨髓来源免疫抑制血管内皮细胞血管生成灌注不足→缺氧→耐药PDAC的"间质屏障"一方面物理阻碍药物渗透，另一方面通过旁分泌信号促进肿瘤进展和耐药——这使基质靶向策略在胰腺癌中具有独特的治疗逻辑。8.2 uPARAP在胰腺癌中的表达模式关键发现：uPARAP不在胰腺癌细胞上，而在CAFs上 根据多组独立研究的一致结论：表达部位uPARAP表达机制**PDAC肿瘤细胞（上皮来源）****阴性** ❌上皮来源癌细胞不表达uPARAP**肿瘤相关成纤维细胞（CAFs）****强阳性** ✅活化的间充质细胞标志**正常胰腺成纤维细胞**低/无静息状态表达受限**胰腺星状细胞（活化后）****上调**活化后转化为肌成纤维细胞表型分子机制：为什么uPARAP在胰腺癌CAFs中上调？ 胰腺癌中CAFs的uPARAP上调涉及以下信号通路：**TGF-β → uPARAP轴**：1. PDAC肿瘤细胞分泌大量TGF-β12. TGF-β1激活CAFs中的TGF-βR/Smad信号3. Smad复合物驱动*MRC2*基因转录上调4. uPARAP蛋白在CAFs表面表达，介导胶原内吞和周转5. 胶原持续重塑促进肿瘤进展和侵袭 此外，胰腺癌微环境中的**缺氧条件（hypoxia）**进一步通过HIF-1α增强CAFs的活化程度和uPARAP表达。8.3 uPARAP-CAFs在胰腺癌进展中的功能角色A. 胶原代谢与基质重塑 uPARAP作为CAFs表面最主要的胶原内吞受体，在胰腺癌间质中执行**胶原双向调控**：功能机制促/抑肿瘤**胶原降解**内吞+溶酶体降解老化胶原片段促进基质更新**新生胶原沉积**清除旧胶原→释放空间→新胶原合成促进纤维化**基质交联调控**与LOX协同调控胶原交联度双向**基质硬度感知**力学信号转导影响CAFs活化状态促进**核心矛盾**：uPARAP的胶原内吞功能在正常组织中维持胶原稳态，但在肿瘤中可能通过"清理旧胶原→为新胶原和肿瘤扩张腾出空间"的方式**反而促进肿瘤进展**。B. 肿瘤免疫微环境调控 uPARAP+ CAFs通过基质重塑间接塑造免疫抑制微环境： 1. **物理屏障**：密集胶原网络阻碍T细胞浸润 2. **细胞因子分泌**：CAFs分泌IL-6、TGF-β、CXCL12等免疫抑制因子 3. **代谢竞争**：CAFs消耗微环境中的关键营养素C. 促进侵袭与转移uPARAP+ CAFs通过基质重塑为肿瘤细胞迁移创造"通道"胶原降解产物可作为趋化因子引导肿瘤细胞定向迁移与VEGFR-2/VEGFR-3相互作用调控淋巴管生成 [3]8.4 CAF靶向ADC策略：旁杀效应的突破性发现 2026年发表在*Molecular Cancer Therapeutics*上的研究首次系统证明了**uPARAP+ CAFs可作为"药物中转站"通过旁杀效应（bystander killing）杀死uPARAP阴性的癌细胞** [11]：核心机制模型 uPARAP ADC静脉给药 ↓ADC结合CAFs表面的uPARAP ↓受体介导快速内吞（5-10分钟） ↓溶酶体中连接子被组织蛋白酶切割 ↓游离payload（MMAE/Dxd）释放至CAFs胞质 ↓Payload穿膜扩散至邻近肿瘤细胞（旁杀效应） ↓uPARAP阴性肿瘤细胞死亡关键实验证据实验模型结果**体外Transwell共培养**uPARAP+成纤维细胞 + EBC-1肺癌细胞~60%肿瘤细胞死亡；uPARAP缺陷成纤维细胞则无效**EBC-1皮下异种移植**肺鳞癌（uPARAP-）6 mg/kg×4 → **所有小鼠完全肿瘤根除**，100天零复发**HT29皮下异种移植**结肠癌（uPARAP-）6 mg/kg → 肿瘤完全消失，但最终复发（不如EBC-1持久）**HT29骨转移模型**骨转移3×6 mg/kg → **显著肿瘤消退**，IVIS信号低于对照100-150倍**Payload普适性验证**9b7-MMAE vs 2h9-Dxd两种payload均有效，Dxd-MMAE机制非特异性**CAFs存活状态**EBC-1治疗前后CAFs本身**未被杀伤**（FAP+成纤维细胞保留），仅作为payload释放"工厂"发现的关键意义 1. **CAFs抵抗ADC自身杀伤**：uPARAP+ CAFs在释放payload后存活——这可能是进化优势（持续释放payload），也可能限制疗效 2. **两株不同抗体（9b7、2h9）均有效**：说明效果是靶点和机制驱动的，非抗体特异 3. **两种不同payload（MMAE、Dxd）均有效**：旁杀效应是普适机制，不局限于微管抑制剂 4. **完全肿瘤根除的可能性**：EBC-1模型中实现100%治愈，提示在某些肿瘤类型中效果显著 5. **肿瘤类型依赖性**：HT29不如EBC-1持久，提示不同肿瘤敏感性不同8.5 胰腺癌作为uPARAP-CAF靶向策略的理想适应症为什么胰腺癌特别适合？胰腺癌特征对uPARAP ADC策略的意义**极高基质比例（50-80%）**CAFs丰度远超其他实体瘤 → 天然payload释放"工厂"密度高**重度TGF-β信号激活**uPARAP在CAFs中表达上调的驱动力强**药物渗透障碍**传统化疗/ADC难以到达肿瘤细胞；CAF靶向从"内部瓦解"屏障**免疫治疗耐药**现有IO方案在PDAC中ORR<5%；ADC旁杀可释放新抗原增强免疫**治疗手段极度匮乏**一线吉西他滨+白蛋白紫杉醇/mFOLFIRINOX后缺乏有效二线方案**临床前证据**结肠癌HT29模型接近PDAC的基质特征，已显示部分疗效PDAC治疗的假想方案策略方案理论基础**uPARAP ADC单药**ADCE-D01类似物利用CAFs→旁杀肿瘤细胞**ADC + 化疗**uPARAP ADC + 吉西他滨/白蛋白紫杉醇化疗削弱基质→增强ADC渗透；协同DNA损伤**ADC + PD-1**uPARAP ADC + 免疫检查点抑制剂ADC旁杀释放新抗原→增强免疫原性**ADC + 抗纤维化**uPARAP ADC + PEGPH20/FAKi先"松动"基质→提高ADC分布8.6 胰腺癌方向的风险与挑战挑战详细分析风险等级**CAFs异质性**并非所有CAFs都高表达uPARAP；炎症型CAF（iCAF）vs 肌成纤维型CAF（myCAF）表达谱不同🟡 中-高**CAFs"双刃剑"**既往Hedgehog抑制剂（如saridegib）去除CAFs后反而加速PDAC进展——CAFs在特定情况下可能抑制肿瘤🔴 **高****旁杀效率**CAFs释放的payload需要穿过致密胶原基质到达肿瘤细胞——PDAC间质比EBC-1模型更致密🟡 中**正常组织CAFs**肝、肺等器官中活化成纤维细胞是否被误伤🟡 中**缺乏PDAC特异性体内模型**当前CAF靶向ADC仅在肺癌/结肠癌模型中验证，PDAC原位模型（KPC）数据缺失🟡 中-高**临床转化路径**需要先建立肉瘤适应症的临床POC，胰腺癌作为后续扩展适应症🟡 中8.7 uPARAP作为胰腺囊性病变生物标志物 一项值得关注的临床研究（NCT036793）正在评估**可溶性uPARAP胞外域（soluble uPARAP）**作为胰腺囊性病变早期恶性转化的生物标志物 [2]。胰腺囊性病变（如IPMN）是PDAC的癌前病变，目前缺乏可靠的无创鉴别手段。如果soluble uPARAP被验证为有效标志物，将同时为uPARAP靶向ADC在PDAC中的开发提供：**患者富集策略**（uPARAP高表达的囊性病变→高危人群→ADC预防/早期干预）**伴随诊断基础**（血清soluble uPARAP + 活检CAFs uPARAP IHC）9. 靶点拓展潜力9.1 已验证的潜在适应症适应症证据强度开发优先级**软组织肉瘤（主适应症）**🟢🟢🟢🟢🟢 临床阶段**最高****骨肉瘤**🟢🟢🟢🟢 临床前体内POC高**胶质母细胞瘤（GBM）**🟢🟢🟢 体外POC中-高**间皮瘤**🟢🟢🟢 表达验证中**AML亚型**🟢🟢🟢 体外+体内POC中**GIST**🟢🟢 表达验证中**CAF基质靶向（乳腺癌/结肠癌/胰腺癌等）**🟢🟢 表达验证中长期9.2 纤维化疾病：理论拓展方向 uPARAP在活化成纤维细胞/肌成纤维细胞中表达，提示其可能成为**抗纤维化治疗**的靶点：潜在适应症理论依据开发状态特发性肺纤维化（IPF）活化成纤维细胞高表达uPARAP学术探索阶段肝纤维化/肝硬化肝星状细胞活化后表达学术探索阶段系统性硬化症皮肤/器官纤维化中肌成纤维细胞学术探索阶段肿瘤微环境重塑CAFs介导的基质重塑已有表达证据⚠️ 纤维化方向的uPARAP靶向尚处于学术假设阶段，无公开的体内药效数据支持。9.3 其他分子形式拓展分子形式理论可行性潜在优势**双特异性ADC**高增强肿瘤选择性**免疫刺激ADC（iADC）**中-高TLR激动剂payload诱导抗肿瘤免疫**放射配体**低-中内吞快但受体循环可能导致同位素排出**CAR-T/CAR-NK**低正常组织成纤维细胞表达可能导致on-target off-tumor毒性**双抗/T细胞engager**低同上风险10. 风险评估10.1 科学风险风险因素等级分析**靶点验证不充分**🟢 **低**多组独立学术团队已验证；体内模型显示完全肿瘤消退**Payload选择**🟡 **中**学术ADC（MMAE）IC50达~5 μg/mL（偏高），ADCE-D01改用P1021 Topo I抑制剂是否有更优疗效待临床验证**肿瘤渗透**🟡 **中**学术ADC虽能显著抑制肿瘤但未完全清除，提示ADC在实体瘤内部分布可能受限**耐药机制**🟡 **中**复发性肿瘤仍保留uPARAP表达（非靶点丢失），复发机制不明**CAF靶向的生物学后果**🟡 **中**杀伤CAFs究竟是抑制还是促进肿瘤进展尚存在学术争议10.2 临床开发风险风险因素等级分析**Phase I数据尚未公布**🟡 **中**2025年6月首例给药至今仅约1年，尚无公开的剂量递增/安全性数据**肉瘤患者招募困难**🟡 **中**STS为罕见肿瘤，年发病率约4-5/10万，多个全球中心可缓解但进度仍受限**剂量优化挑战**🟡 **中**Topo I抑制剂payload（类似Dato-DXd/SG）需平衡疗效与血液学毒性**单药 vs 联合策略**🟢 **低**已获得Fast Track/ODD，单药上市路径清晰；后续联合策略锦上添花10.3 商业与竞争风险风险因素等级分析**单一靶点公司**🟡 **中**Adcendo虽有三条管线，但uPARAP为其最原创靶点；ADCE-T02（TF）竞争激烈**融资依赖**🟡 **中**累计融资~$300M支撑三条管线至关键临床里程碑，后续仍需资金**大药企竞争**🟢 **低**uPARAP暂未被大药企关注，先发优势明显**商业化能力**🟡 **中**Adcendo为biotech，缺乏商业化基础设施；未来需partner或被收购**技术授权风险**🟡 **中**linker-payload技术来自Duality Biologics，存在授权协议条款约束10.4 监管风险风险因素等级分析**加速审批路径**🟢 **低**Fast Track + ODD双重加速，监管路径清晰**替代终点接受度**🟡 **中**ORR作为肉瘤加速审批终点的FDA接受度因亚型而异**确证性试验要求**🟡 **中**加速批准后需确证性PFS/OS数据11. 总结与展望11.1 核心结论 uPARAP是一个**全球独家、高度差异化**的新型ADC靶点，具备以下核心投资/研究论点： 1. **靶点生物学优异**：组成型快速内吞+直接溶酶体递送机制在临床阶段ADC靶点中独树一帜，理论上可实现极高的payload递送效率。 2. **临床前数据强健**：两组独立学术团队验证了uPARAP ADC的体内概念——系统性给药实现100%完全肿瘤消退；原发灶+转移灶双重抑制效果显著。 3. **临床开发无直接竞争者**：Adcendo为全球唯一临床阶段uPARAP药物开发者，享有至少5年以上的时间窗口。 4. **监管路径清晰**：FDA Fast Track + Orphan Drug双重认定，为加速审批铺平道路。 5. **资本支持充足**：累计~$300M融资，顶级VC syndicate背书，三条管线并行推进。 6. **适应症选择精准**：软组织肉瘤（STS）为罕见肿瘤、高度未满足需求，且肉瘤ADC领域竞争相对温和。11.2 关键待观察里程碑预期时间里程碑重要性2026年下半年ADCElerate1剂量递增初步安全性数据⭐⭐⭐⭐⭐ **最高**2026-2027年首个ORR/DOR疗效信号读出⭐⭐⭐⭐⭐2027年RP2D确定 + 剂量扩展队列启动⭐⭐⭐⭐2027-2028年关键学术会议数据公布（ASCO/ESMO/CTOS）⭐⭐⭐⭐2028-2029年潜在加速审批BLA/MAA提交⭐⭐⭐11.3 总体评分维度评分（5分制）靶点新颖性⭐⭐⭐⭐⭐靶点验证强度⭐⭐⭐⭐临床前数据质量⭐⭐⭐⭐⭐竞争格局优势⭐⭐⭐⭐⭐临床数据成熟度⭐⭐（数据尚未公布）监管路径清晰度⭐⭐⭐⭐团队/资本实力⭐⭐⭐⭐商业化潜力⭐⭐⭐（肉瘤为niche市场）**综合****⭐⭐⭐⭐**参考文献 [1] Nielsen CF, et al. "The collagen receptor uPARAP/Endo180 as a novel target for antibody-drug conjugate mediated treatment of mesenchymal and leukemic cancers." *Oncotarget*, 2017. DOI: 10.18632/oncotarget.17883. [2] Melander MC, et al. "uPARAP/Endo180: a multifaceted protein of mesenchymal cells." *Cellular and Molecular Life Sciences*, 2022. DOI: 10.1007/s00018-022-04249-7. [3] Durré T, et al. "uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis." *Nature Communications*, 2018. DOI: 10.1038/s41467-018-07514-1. [4] Yeo XL, et al. "Endo180 (MRC2) Antibody–Drug Conjugate for the Treatment of Sarcoma." *Molecular Cancer Therapeutics*, 2023. DOI: 10.1158/1535-7163.MCT-22-0514. [5] Adcendo ApS. "First Patient Dosed in Phase I/II ADCElerate1 Trial of ADCE-D01." Press Release, June 10, 2025. [6] Adcendo ApS. "FDA Fast Track Designation Granted to ADCE-D01 for Soft Tissue Sarcoma." Press Release, October 2025. [7] Adcendo ApS. "Pipeline Progress and Recent Achievements Update." Press Release, April 20, 2026. [8] Adcendo ApS. "$135 Million Series B Financing." Press Release, November 25, 2024. [9] Adcendo ApS. "$75 Million Series C Financing." Press Release, April 14, 2026. [10] ClinicalTrials.gov. NCT06797999 — "First-in-Human Study of ADCE-D01 in Soft Tissue Sarcoma (ADCElerate1)." [11] Nørregaard KS, Jürgensen HJ, Gårdsvoll H, et al. "The Recycling Collagen Receptor uPARAP Is a Unique Mediator of CAF-Targeted ADC Bystander Killing in Carcinoma." *Molecular Cancer Therapeutics*, 2026. DOI: 10.1158/1535-7163.MCT-25-0554. [12] Chinese Clinical Trial Registry. ChiCTR2500112345 — "A Phase I clinical study of BL-M24D1 in patients with NSCLC and other solid tumors." [13] ClinicalTrials.gov. NCT07255898 — "A Study of BL-M24D1 in Patients With Relapsed or Refractory Multiple Myeloma and Other Hematologic Malignancies." [14] Melander MC, et al. "uPARAP/Endo180: a multifaceted protein of mesenchymal cells." *Cellular and Molecular Life Sciences*, 2022. Section on CAF-specific targeting.**免责声明**: 本报告基于公开文献和公司披露信息编写，仅供专业研究参考，不构成任何投资建议。临床阶段药物开发存在高度不确定性，实际结果可能与预期存在重大差异。

Sol-Gel received a Notice of Allowance for a method-of-use patent extending intellectual property protection for topical patidegib (SGT-610) until 2044 Sol-Gel completed an oversubscribed underwritten offering, raising gross proceeds of approximately $33.1 million from leading healthcare specialist investors Pivotal Phase 3 clinical trial of SGT-610 (patidegib gel, 2%) for Gorlin syndrome remains ongoing, with top-line results on track for anticipated readout in the fourth quarter of 2026 Sol-Gel signed an exclusive license agreement with Sun Pharmaceutical Industries Ltd. for the commercialization of TWYNEO® in India NESS ZIONA, Israel, May 28, 2026 (GLOBE NEWSWIRE) -- Sol-Gel Technologies, Ltd. (NASDAQ: SLGL), a dermatology company, pioneering treatments for patients with rare and severe skin conditions, today announced financial results for the first quarter ended March 31, 2026, and provided a corporate update. Q 1 202 6 and Recent Corporate Developments In May 2026, the company received a Notice of Allowance (U.S. Patent Application No. 19/266,342) from the U.S. Patent and Trademark Office for our patent application covering a method-of-use that is critical to successful topical patidegib therapy. This patent will provide protection for SGT-610 until 2044. In March 2026, Sol-Gel closed an underwritten offering resulting in aggregate gross proceeds of approximately $33.1 million. The offering included participation from new and existing investors, including Great Point Partners, LLC, Trails Edge Capital Partners, Surveyor Capital (a Citadel company), Affinity Asset Advisors, Squadron Capital Management, Stonepine Capital Management and AuGC BioFund. TD Cowen and LifeSci Capital acted as joint book-running managers for the offering. Sol-Gel’s pivotal Phase 3 clinical trial of SGT-610 (patidegib gel, 2%) for Gorlin syndrome continues to advance, and the Company remains on track to report top-line results in the fourth quarter of 2026; preparations for a proof-of-concept study of SGT-610 in HF-BCC are ongoing. In April 2026, Sol-Gel entered into an exclusive license agreement with Sun Pharmaceutical Industries Ltd. for the commercialization of TWYNEO® in India. This agreement is in addition to the eight agreements for the commercialization of TWYNEO® and EPSOLAY Sol-Gel signed during 2024 and 2025 in various territories covering most European countries, South Africa, South Korea, Australia and New Zealand. These already signed agreements, together with agreements we anticipate signing in the future covering Latin American countries, Spain and Portugal, have the potential to provide upfront and regulatory milestone payments of up to $4.5 million. The above excludes Sol-Gel's previously signed agreements with Beimei Pharma (China, Hong Kong, Macau, Taiwan and Israel) and Searchlight Pharma (Canada). Based on the forecasts received from Sol-Gel’s current and potential partners, Sol-Gel now expects that TWYNEO and EPSOLAY will launch in the majority of these new territories during 2028 and 2027 respectively, and following launch, these transactions are anticipated to provide Sol-Gel with an annual royalty revenue stream with the potential to reach approximately $10 million by 2031 and potentially grow in subsequent years. Mr. Mori Arkin , E xecutive Chairman of Sol-Gel, stated : “The first quarter of 2026 was a period of substantial progress on every front that matters to Sol-Gel. The Notice of Allowance extending the exclusivity of patidegib until 2044 marks a major milestone in the value creation of SGT-610 and Sol-Gel as a company. In parallel, the successful completion of our oversubscribed offering, with broad participation from leading healthcare specialist investors, is expected to provide Sol-Gel with the financial resources to support operations into 2028, allowing us to execute our Phase 3 program of SGT-610 through top-line readout and to support its pre-commercialization activities." Mr. Arkin further commented : "We believe that the combination of our March 2026 financing and the Notice of Allowance for a method-of-use patent protecting topical patidegib until 2044 fundamentally reshapes the long-term opportunity for SGT-610. We now have both the capital and intellectual property runway to pursue the prevention of new BCCs in Gorlin syndrome, for which top-line results are expected in the fourth quarter of 2026. We continue to be excited about the potential of the high-frequency BCC indication, which could double the commercial potential of patidegib, and we look forward to initiating a proof-of-concept study." Lastly, Mr. Arkin commented : "The license agreement with Sun Pharma for India, one of the largest dermatology markets in the world, is another important step in unlocking the global value of TWYNEO through partnerships with leading companies in their respective territories. While the commercialization of our legacy products is a non-core business of Sol-Gel, we believe that this activity has the potential to become an asset of substantial value, in the not-too-distant future. At the appropriate time, we plan to monetize this business and use the non-dilutive funds to support our long-term strategy of developing innovative treatments for unmet medical needs in dermatology." Financial Results for the First Quarter 202 6 Revenue for the first quarter was $0.1 million, compared to revenue of $1.0 million for the same period in 2025. The decrease is mainly attributed to a milestone payment from Searchlight in the first quarter of 2025. Research and development expenses were $2.8 million compared to $8.8 million for the same period in 2025. The decrease of $6.0 million was primarily attributed to a decrease of $3.9 million due to expenses associated with supplier-led manufacturing development to support future commercialization of SGT-610 in the first quarter of 2025, a decrease of $1.1 million in clinical trial expenses related to SGT-610 and a decrease of $0.8 million in expenses related to the manufacturing development of EPSOLAY and TWYNEO. General and administrative expenses were $1.2 million compared to $1.3 million for the same period in 2025. Sol-Gel reported a net loss of $3.7 million for the first quarter of 2026 and loss of $1.31 per basic and diluted share, compared to a net loss of $8.8 million and loss of $3.2 per basic and diluted share for the same period in 2025. As of March 31, 2026, Sol-Gel had $10.1 million in cash, cash equivalents, and deposits and $42.7 million in marketable securities, for a total balance of $52.8 million. The Company expects its cash resources to fund cash requirements into the first quarter of 2028. About Sol-Gel Technologies Sol-Gel is a specialized dermatology company advancing innovative therapies for rare and serious skin diseases. Its lead investigational candidate, SGT-610 (patidegib gel, 2%), is a Phase 3, orphan- and breakthrough-designated topical hedgehog inhibitor being developed for the prevention of new basal cell carcinoma (BCC) lesions in patients with Gorlin syndrome, with the potential to offer an improved safety pro to oral hedgehog inhibitors. Subject to regulatory approval in Gorlin syndrome, SGT-610 may also represent a future opportunity in high-frequency BCC. Sol-Gel is also advancing SGT-210, an investigational topical EGFR inhibitor for indications with significant unmet need, and has developed two FDA-approved dermatology products, TWYNEO® and EPSOLAY®. Forward Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements. including, but not limited to statements regarding the timing of clinical milestones for the Phase 3 program of SGT-610 in Gorlin syndrome, the Company’s cash runway, the timing of the launch of the commercialization of TWYNEO® and EPSOLAY in various territories and the anticipated financial benefits of the Company’s agreements for the commercialization of TWYNEO® and EPSOLAY. In some cases, you can identify forward-looking statements by terminology such as “believe,” “may,” “estimate,” “continue,” “anticipate,” “intend,” “should,” “plan,” “expect,” “predict,” “potential,” or the negative of these terms or other similar expressions. Forward-looking statements are based on information we have when those statements are made or our management’s current expectations and are subject to risks and uncertainties that could cause actual performance or results to differ materially from those expressed in or suggested by the forward-looking statements. Important factors that could cause such differences include, but are not limited to, the risk of a delay in reporting the top-line results of Sol-Gel’s pivotal Phase 3 clinical trial of SGT-610 (patidegib gel, 2%) for Gorlin syndrome, that we will not successfully complete the Gorlin Phase 3 trial or the success of our clinical trials, a delay in the launch of the commercialization of TWYNEO® and EPSOLAY in various territories, that the financial benefits of the Company’s agreements for the commercialization of TWYNEO® and EPSOLAY will not be as anticipated as well as the following factors: (i) the adequacy of our financial and other resources, particularly in light of our history of recurring losses; (ii) our ability to complete the development of our product candidates; (iii) our ability to find suitable co-development partners; (iv) our ability to obtain and maintain regulatory approvals for our product candidates in our target markets, the potential delay in receiving such regulatory approvals and the possibility of adverse regulatory or legal actions relating to our product candidates even if regulatory approval is obtained; (v) our collaborators’ ability to commercialize our pharmaceutical product candidates; (vi) our ability to obtain and maintain adequate protection of our intellectual property; (vii) our collaborators’ ability to manufacture our product candidates in commercial quantities, at an adequate quality or at an acceptable cost; (viii) our collaborators’ ability to establish adequate sales, marketing and distribution channels; (ix) acceptance of our product candidates by healthcare professionals and patients; (x) the possibility that we may face third-party claims of intellectual property infringement; (xi) the timing and results of clinical trials that we may conduct or that our competitors and others may conduct relating to our or their products; (xii) intense competition in our industry, with competitors having substantially greater financial, technological, research and development, regulatory and clinical, manufacturing, marketing and sales, distribution and personnel resources than we do; (xiii) potential product liability claims; (xiv) potential adverse federal, state and local government regulation in the United States, China, Europe or Israel; and (xv) loss or retirement of key executives and research scientists; (xvi) general market, political and economic conditions in the countries in which the Company operates; and, (xvii) the security situation in Israel. These factors and other important factors discussed in the Company's Annual Report on Form 20-F filed with the Securities and Exchange Commission (“SEC”) on March 19, 2026, and our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Except as required by law, we undertake no obligation to update any forward-looking statements in this press release. SOL-GEL TECHNOLOGIES LTD. CONDENSED CONSOLIDATED BALANCE SHEETS (U.S. dollars in thousands) (Unaudited) December 31, March 31, 2025 2026 Assets CURRENT ASSETS: Cash and cash equivalents $ 11,033 $ 10,136 Marketable securities 12,966 42,692 Accounts receivables 1,968 1,067 Prepaid expenses and other current assets 1,004 1,894 TOTAL CURRENT ASSETS 26,971 55,789 NON-CURRENT ASSETS: Restricted long-term deposits and cash equivalents 1,324 1,328 Property and equipment, net 140 136 Operating lease right-of-use assets 1,027 901 Other long-term assets 62 - Funds in respect of employee rights upon retirement 393 396 TOTAL NON-CURRENT ASSETS 2,946 2,761 TOTAL ASSETS $ 29,917 $ 58,550 Liabilities and shareholders' equity CURRENT LIABILITIES: Accounts payable $ 735 $ 782 Other accounts payable 4,941 5,046 Current maturities of operating leases 495 485 TOTAL CURRENT LIABILITIES 6,171 6,313 LONG-TERM LIABILITIES: Operating leases liabilities 496 377 Liability for employee rights upon retirement 439 454 TOTAL LONG-TERM LIABILITIES 935 831 TOTAL LIABILITIES $ 7,106 $ 7,144 SHAREHOLDERS' EQUITY: Ordinary shares, NIS 1 par value – authorized: 5,000,000 as of December 31, 2025 and March 31, 2026, respectively; issued and outstanding: 2,786,158 and 3,268,991 as of December 31, 2025 and March 31, 2026, respectively 774 1,321 Additional paid-in capital 259,047 290,822 Accumulated deficit (237,010 ) (240,737 ) TOTAL SHAREHOLDERS' EQUITY 22,811 51,406 TOTAL LIABILITIES AND SHAREHOLDERS' EQUITY $ 29,917 $ 58,550 SOL-GEL TECHNOLOGIES LTD. CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (U.S. dollars in thousands) (Unaudited) Three months ended March 31 2025 2026 REVENUES $ 1,031 $ 108 RESEARCH AND DEVELOPMENT EXPENSES 8,843 2,786 GENERAL AND ADMINISTRATIVE EXPENSES 1,257 1,177 OPERATING LOSS 9,069 3,855 FINANCIAL INCOME, net (261 ) (128 ) LOSS FOR THE PERIOD 8,808 3,727 BASIC AND DILUTED LOSS PER ORDINARY SHARE 3.2 1.31 WEIGHTED AVERAGE NUMBER OF SHARES OUTSTANDING USED IN COMPUTATION OF BASIC AND DILUTED LOSS PER SHARE * 2,785,762 2,836,907 * The accompanying notes are an integral part of these unaudited condensed consolidated financial statements. Sol-Gel I nvestor Relations : Eyal Ben-Or Chief Financial Officer ir@sol-gel.com