Fluorouracil

Results demonstrated favorable safety, injection feasibility, and encouraging oncologic outcomes in patients (n=22) with locally advanced or borderline resectable pancreatic cancer Median Overall Survival of 23 months from date of diagnosis [95% CI; 17 months – not reached] Median Local Progression-Free Survival of 13.3 months from completion of radiation Notable findings observed in exploratory biomarker analyses include: An association between increased circulating tumor mutational burden (cTMB) and LPFS and OS CA19-9 normalization in 59% of patients in the study, and an association between CA19-9 normalization and OS First patient injected in a new cohort that adds standard-of-care concurrent chemotherapy (capecitabine or 5-FU) to radiotherapy-activated JNJ-1900 (NBTXR3) and recruitment is ongoing Investigators concluded that these results support further evaluation in a randomized study An association between increased circulating tumor mutational burden (cTMB) and LPFS and OS CA19-9 normalization in 59% of patients in the study, and an association between CA19-9 normalization and OS Data presented at the 2025 Annual Meeting of the European Society of Radiation Oncology PARIS and CAMBRIDGE, Mass., May 05, 2025 (GLOBE NEWSWIRE) -- NANOBIOTIX (Euronext: NANO –– NASDAQ: NBTX – the ‘‘Company’’), a late-stage clinical biotechnology company pioneering nanotherapeutic approaches to improve treatment outcomes for patients with cancer, today announced the presentation of full results from the completed dose escalation and dose expansion phases of a Phase 1 study evaluating JNJ-1900 (NBTXR3) in patients with locally advanced or borderline resectable pancreatic cancer. The study, conducted by The University of Texas MD Anderson Cancer Center (“MD Anderson”), was presented by principal investigator Dr. Eugene Koay at the 2025 Annual Meeting of the European Society for Radiotherapy and Oncology (ESTRO 2025). Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by aggressive tumor biology and limited responsiveness to standard therapies. For patients with locally advanced (“LAPC”) or borderline resectable (“BRPC”) disease, the current standard-of-care (“SOC”)—induction chemotherapy followed by chemoradiation—rarely delivers curative outcomes, underscoring the need for novel treatment approaches. “Patients with locally advanced or borderline resectable pancreatic cancer face a particularly urgent unmet need for therapeutic innovation that can provide a meaningful survival benefit with an acceptable safety profile,” said Eugene Koay, MD, PhD, Associate Professor of Radiation Oncology at MD Anderson. “We are encouraged by the results from the completed cohorts and look forward to the continued evaluation of JNJ-1900 (NBTXR3) in combination with standard-of-care chemoradiation after induction chemotherapy.” PRESENTATION #E25-2265: NANORAY Pancreas: A Phase 1 Study of NBTXR3 (JNJ-1900) Activated by Radiotherapy for Locally Advanced or Borderline Resectable Pancreatic Cancer (LAPC or BRPC)Koay EJ, Liu S, Guerrero P, Stokes E, Katz MHG, Ikoma N, Snyder RA, Tzeng CD, Overman MJ, Pant S, Wolff RA, Javle M, Holliday EB, Ludmir EB, Das P, Noticewala S, Koong AC, Tamm EP, Bhutani M This MD Anderson-sponsored Phase 1 study evaluated the potential of radiotherapy(“RT”)-activated JNJ-1900 (NBTXR3) activated by radiation therapy (45 Gy in 15 fractions) to overcome inherent radioresistance in patients with LAPC or BRPC. The majority of patients in the study (20/22) were diagnosed with locally advanced, unresectable disease (LAPC). For clarity, patients with LAPC or BRPC are traditionally treated with induction chemotherapy followed by concurrent chemoradiation. The treatment regimen in the completed dose escalation and dose expansion parts of this Phase 1 study replaced concurrent chemoradiation with RT-activated JNJ-1900 (NBTXR3) after induction chemotherapy. Key Results: Favorable safety profile and injection feasibility were observed (n=22) Median overall survival (“mOS”): 23 months from diagnosis [95% CI; 17 months – not reached] For context, an MD Anderson historical review of 144 patients with LAPC treated at the same center showed a mOS of 19.2 months. Patients in the historical review received induction chemotherapy followed by RT with or without concurrent or maintenance chemotherapy (80% received RT with concurrent chemotherapy) Median local progression-free survival (“mLPFS”): 13.3 months from completion of radiation Two LAPC patients achieved R0 surgical resection For context, an MD Anderson historical review of 144 patients with LAPC treated at the same center showed a mOS of 19.2 months. Patients in the historical review received induction chemotherapy followed by RT with or without concurrent or maintenance chemotherapy (80% received RT with concurrent chemotherapy) Exploratory Biomarker Analyses: Of the 20 patients for whom circulating Tumor Mutational Burden (cTMB) data was available, a notable proportion (40%; 8/20) exhibited increased cTMB, and investigators observed an association between increased cTMB and improved LPFS and OS Normalization of CA19-9, a surrogate for overall survival benefit, was observed in 59% of patients (11/22) and was associated with longer survival in the study. For context, an MD Anderson historical review of 243 patients with LAPC treated at the same center showed normalization of CA19-9 in approximately 17% of patients treated with the standard of care who had elevated CA19-9 levels at diagnosis For context, an MD Anderson historical review of 243 patients with LAPC treated at the same center showed normalization of CA19-9 in approximately 17% of patients treated with the standard of care who had elevated CA19-9 levels at diagnosis Based on the safety and preliminary efficacy findings, investigators concluded that further evaluation of JNJ-1900 (NBTXR3) is warranted in a randomized study. “Our collaboration with MD Anderson has always been driven by a shared commitment to exploring bold new approaches for patients with high unmet need,” said Louis Kayitalire, MD, Chief Medical Officer at Nanobiotix. “Given the extremely poor survival rates in LAPC and BRPC, the results from this Phase 1 study give us confidence in the potential of JNJ-1900 (NBTXR3) to serve as a meaningful addition to the treatment landscape. We are particularly excited about the potential to further enhance outcomes through combination of JNJ-1900 (NBTXR3) with SOC chemoradiation in the study’s new active cohort, and we look forward to advancing this program in pancreatic cancer.” MD Anderson received FDA clearance to expand the study to include a new cohort that combines of JNJ-1900 (NBTXR3) with SOC concurrent chemoradiation after induction chemotherapy. The first patient in the new cohort has been injected, and recruitment is ongoing. Nanobiotix Conference Call Nanobiotix will host a conference call and webcast featuring Nanobiotix Chief Executive Officer and Chairman of the Executive Board, Laurent Levy, to discuss the data on Monday May 5th, 2025, at 8:00 AM EDT / 2:00 PM CEST. Details for the call are as follows: Webcast link: click here Audio-only dial-in link: click here Participants can use the audio-only link above to register and obtain dial-in instructions to listen to the presentation via phone and ask questions during the Q&A session, or participants can use the webcast link to register and listen and watch the slide presentation online; the replay version will be available under the same webcast link shortly after the presentation and will be archived on the Company’s website at www.nanobiotix.com. It is recommended to join 10 minutes prior to the event start. Participants are invited to email their questions in advance to investors@nanobiotix.com. About JNJ-1900 (NBTXR3) JNJ-1900 (NBTXR3) is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide nanoparticles that is administered via one-time intratumoral injection and activated by radiotherapy. Its proof-of-concept was achieved in soft tissue sarcomas through a successful randomized Phase 2/3 study in 2018. The product candidate’s physical mechanism of action (MoA) is designed to induce significant tumor cell death in the injected tumor when activated by radiotherapy, subsequently triggering adaptive immune response and long-term anti-cancer memory. Given the physical MoA, Nanobiotix believes that JNJ-1900 (NBTXR3) could be scalable across any solid tumor that can be treated with radiotherapy and across any therapeutic combination, particularly immune checkpoint inhibitors. Radiotherapy-activated JNJ-1900 (NBTXR3) is being evaluated across multiple solid tumor indications as a single agent or combination therapy. The program is led by NANORAY-312—a global, randomized Phase 3 study in locally advanced head and neck squamous cell cancers. In February 2020, the United States Food and Drug Administration granted regulatory Fast Track designation for the investigation of JNJ-1900 (NBTXR3) activated by radiation therapy, with or without cetuximab, for the treatment of patients with locally advanced HNSCC who are not eligible for platinum-based chemotherapy—the same population being evaluated in the Phase 3 study. Given the Company’s focus areas, and balanced against the scalable potential of NBTXR3, Nanobiotix has engaged in a collaboration strategy to expand development of the product candidate in parallel with its priority development pathways. Pursuant to this strategy, in 2019 Nanobiotix entered into a broad, comprehensive clinical research collaboration with The University of Texas MD Anderson Cancer Center to sponsor several Phase 1 and Phase 2 studies evaluating JNJ-1900 (NBTXR3) across tumor types and therapeutic combinations. In 2023, Nanobiotix announced a license agreement for the global co-development and commercialization of JNJ-1900 (NBTXR3) with Janssen Pharmaceutica NV, a Johnson & Johnson company. About NANOBIOTIX Nanobiotix is a late-stage clinical biotechnology company pioneering disruptive, physics-based therapeutic approaches to revolutionize treatment outcomes for millions of patients; supported by people committed to making a difference for humanity. The Company’s philosophy is rooted in the concept of pushing past the boundaries of what is known to expand possibilities for human life. Incorporated in 2003, Nanobiotix is headquartered in Paris, France and is listed on Euronext Paris since 2012 and on the Nasdaq Global Select Market in New York City since December 2020. The Company has subsidiaries in Cambridge, Massachusetts (United States) amongst other locations. Nanobiotix is the owner of more than 25 umbrella patents associated with three (3) nanotechnology platforms with applications in 1) oncology; 2) bioavailability and biodistribution; and 3) disorders of the central nervous system. For more information about Nanobiotix, visit us at www.nanobiotix.com or follow us on LinkedIn and Twitter Disclaimer This press release contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the use of proceed therefrom, and the period of time through which the Company’s anticipates its financial resources will be adequate to support operations. Words such as “expects”, “intends”, “can”, “could”, “may”, “might”, “plan”, “potential”, “should” and “will” or the negative of these and similar expressions are intended to identify forward-looking statements. These forward-looking statements which are based on the Company’ management’s current expectations and assumptions and on information currently available to management. These forward-looking statements involve known and unknown risks, uncertainties and other factors that could cause actual results to differ materially from those implied by the forward-looking statements, including risks related to Nanobiotix’s business and financial performance, which include the risk that assumptions underlying the Company’s cash runway projections are not realized. Further information on the risk factors that may affect company business and financial performance is included in Nanobiotix’s Annual Report on Form 20-F filed with the SEC on April 02, 2025 under “Item 3.D. Risk Factors”, in Nanobiotix’s 2024 universal registration document filed with the AMF on April 02, 2025,, and subsequent filings Nanobiotix makes with the SEC from time to time which are available on the SEC’s website at www.sec.gov. The forward-looking statements included in this press release speak only as of the date of this press release, and except as required by law, Nanobiotix assumes no obligation to update these forward-looking statements publicly. Contacts Attachment 2025-05-05 -- NBTX -- Full Ph1 NBTXR3 Results in Pancreatic Cancer -- FINAL

随着抗体药物偶联物（ADCs）的迅速发展，目前已有12种ADC获得FDA批准，另有超过280种不同的ADC处于临床开发阶段。尽管在ADC药物的研发上取得了一定的成功，但仍然存在重大挑战。特别是，将临床前研究结果转化为临床应用仍然十分困难。这是因为许多ADC常与血液学毒性相关，这种毒性可能是由于ADC直接杀伤造血细胞，或由在身体其他部位释放的载荷间接引起的。因此，开发能够预测临床结果的体外检测方法成为ADC药物向临床转化的不可或缺的条件。近日的AACR大会上，Zymeworks公布开发了一种可能会改善ADC的开发，并指导选择最优的连接子和载荷的体外预测血液学毒性的方法。图1. 骨髓来源的造血干细胞/祖细胞在正常分化为谱系特异性细胞及其相关血液学毒性过程中的细胞层级结构示意图。研究方法Zymeworks测试了不同的抗体药物偶联物（ADC）载荷（exatecan、DXd、SN-38、ZD06519、DM1、DM4、MMAE、MMAF），以了解游离载荷本身对非靶向毒性的影响。通过将靶向抗体和非靶向抗体与一种共同的hemiasterlin微管抑制剂偶联，同时改变可被蛋白酶切割的连接子，生成了不同的ADC，以评估连接子对靶向和非靶向细胞毒性在体外的影响。并且在最后，Zymeworks测试了两种具有相同药物-连接子的临床验证的ADC，以评估抗体在ADC非靶向毒性中的影响。图2. 抗体药物偶联物（ADC）的示意图，使用这些ADC进行了克隆形成、可切割性、细胞毒性以及/或体外稳定性检测。Telisotuzumab和Palivizumab ADC的药物抗体比（DAR）为4（±0.2），而Trastuzumab和Patritumab ADC的DAR分别为7.8和7.7。人源克隆形成细胞（CFC）检测能够预测某些与抗体药物偶联物（ADCs）相关的临床毒性。Zymeworks从骨髓中分离出健康的CD34⁺造血干细胞，并与多种细胞因子共同培养，以诱导其分化为红系（BFU-E）、髓系（CFUGM）或巨核系（CFU-Mk）祖细胞，随后用不同浓度的抗体药物偶联物（ADC）、载荷或仅用制剂缓冲液（溶剂对照）进行处理。孵育后，计数克隆数量，并通过比较处理组与溶剂对照组的克隆数量，确定克隆抑制百分比。图3. 克隆形成细胞（CFC）检测流程的示意图。载荷——ADC载荷对人类红系、髓系和巨核系祖细胞具有不同的固有细胞毒性。图4. 在克隆形成细胞（CFC）检测中（如图3所示），游离拓扑异构酶1抑制剂（TOPO1i）和微管抑制剂（MTI）载荷的体外细胞毒性。上图的结果显示，Exatecan在CFC检测中表现出比其他TOPO1i载荷更高的细胞毒性。类似地，对于MTI载荷，DM4和MMAE显示出最高的细胞毒性，其次是DM1和MMAF。连接子——比较具有相同抗体和载荷但不同连接子的非靶向ADC，突出了连接子对非靶向毒性的潜在影响。表1. 不同ADC在克隆形成细胞（CFC）检测中的细胞毒性（EC₅₀，单位为nM，检测方法如图3所示）。抗体——比较具有相同载荷和连接子但不同抗体的ADC，突出了抗体对非靶向毒性的潜在贡献。图5. 克隆形成细胞（CFC）检测（如图3所示）。图中显示，Patritumab deruxtecan（HER3-DXd）表现出比Trastuzumab deruxtecan（T-DXd）更高的细胞毒性，这与在临床环境中接受HER3-DXd治疗的患者相比接受T-DXd治疗的患者出现更高发生率的血液学毒性的观察结果一致（参考文献1、2）。体外连接子切割和细胞毒性检测揭示了不同的载荷释放动力学。不同的连接子在溶酶体检测中以不同的速率释放载荷，如下图所示。图6. 通过将相应的测试样品（1-3 μM）加入到人溶酶体提取液中，测量了来自抗体药物偶联物（ADCs）的释放载荷。释放的载荷通过液相色谱-质谱（LC-MS）进行测定。P.L.Salomon等人（参考文献3）也报告了在生化检测中连接子切割速率与体外细胞毒性之间存在显著的不一致性。对带有不同连接子的cMet和palivizumab的半花碱类抗体药物偶联物（ADCs）的体外评估突出了靶向依赖性细胞毒性以及某些连接子的不稳定性。表2. 靶向ADC与非靶向ADC的体外细胞毒性及培养基中稳定性比较。对于细胞毒性检测，癌细胞用测试样品的梯度稀释液处理，并在标准培养条件下孵育4天。处理后，通过ATP定量荧光试剂测定细胞活性。对于ADC在生长培养基中的稳定性检测，将EBC-1癌细胞在标准培养条件下培养4天后，收集培养基（RPMI 1640培养基，添加10%胎牛血清），随后通过离心去除细胞和杂质。ADC在生长培养基中以1.4 μM的浓度孵育4天，并通过质谱法测定载荷释放量（占理论值的百分比）。结论能够预测临床毒性特征非常重要，这一特征在很大程度上取决于载荷类别以及抗体药物偶联物（ADC）的关键属性。临床前研究结果难以有效预测ADC的临床毒性，导致ADC设计需要在患者中进行经验性测试。使用原代骨髓细胞的克隆形成细胞（CFC）检测可用于评估ADC及其载荷对血液祖细胞系的毒性。将ADC的临床毒性与体外CFC检测结果进行比较表明，CFC检测能够有效重现特定的临床观察结果，使其成为ADC筛选的有价值工具。由于ADC在人体内的复杂代谢过程，预测ADC的临床毒性特征仍然是一个复杂的挑战。简单了解--ZymeworksZymeworks是一家全球性的生物技术公司，致力于开发用于治疗难治性疾病的新型多功能治疗药物，包括癌症、炎症和自身免疫性疾病。Zymeworks正凭借其在抗体药物偶联物和多特异性抗体治疗药物领域的经验和能力，快速推进丰富的产品管线，覆盖多个具有重大未满足医疗需求的适应症中的新型靶点。除了拥有完全自主的管线外，Zymeworks还拥有Azymetric™技术平台，通过与全球生物制药公司的战略合作伙伴关系，在产品开发中得到了进一步的利用和临床验证。参考文献1. I. E. Krop et al. J. Clin. Oncol. 2023, 41, 5550-55602. S. Modi et al. N. Engl. J. Med. 2020, 382, 610-6213. P. L. Salomon et al. Pharmaceutics 2019, 16, 4817-4825基础知识点供给站：Exatecan（依喜替康）：一种DNA拓扑异构酶I抑制剂（Topoisomerase I inhibitor），通过抑制拓扑异构酶I的活性，干扰癌细胞的DNA复制和修复过程，从而发挥抗癌作用。主要用于癌症治疗研究，包括结直肠癌、肺癌、乳腺癌等。它可以单独使用，也可以与其他药物（如氟尿嘧啶类药物）联合使用，能够显著延长患者的生存期，提高生活质量。DM4：一种细胞毒性美登素类药物，是美登素（maytansine）的结构类似物，含有巯基（-SH）。它通过抑制微管蛋白聚合和微管组装，增强微管的不稳定性，从而有效抑制微管动力学，导致有丝分裂阻滞和细胞凋亡。主要用于制备抗体药物偶联物（ADC），通过二硫键将美登素与抗体连接起来，用于癌症的靶向治疗。MMAE（Monomethyl auristatin E）：一种合成的微管蛋白抑制剂，属于奥瑞他汀类药物。它通过与微管蛋白结合，阻止微管的聚合，从而抑制细胞的有丝分裂，导致细胞周期阻滞和细胞凋亡。广泛用于抗体药物偶联物（ADC）的开发，作为载荷部分，通过抗体将药物精准递送到癌细胞中，发挥高效的细胞毒性作用。DM1（Mertansine）：一种美登素类药物，是一种强效的微管蛋白抑制剂。它通过与微管蛋白结合，抑制微管的动态性，从而阻止细胞的有丝分裂。DM1是最早用于抗体药物偶联物（ADC）的载荷之一，例如在T-DM1（Ado-trastuzumab emtansine）中，DM1通过连接子与抗体结合，用于治疗HER2阳性乳腺癌。欢迎感兴趣的朋友进群讨论，群二维码如下：推文用于传递知识，如因版权等有疑问，请于本文刊发30日内联系医药速览。原创内容未经授权，禁止转载至其他平台。有问题可发邮件至yong_wang@pku.edu.cn获取更多信息。©2021 医药速览 保留所有权利往期链接“小小疫苗”养成记 | 医药公司管线盘点 人人学懂免疫学| 人人学懂免疫学（语音版）综述文章解读 | 文献略读 | 医学科普|医药前沿笔记PROTAC技术| 抗体药物| 抗体药物偶联-ADC核酸疫苗 | CAR技术| 化学生物学温馨提示医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群请扫描上方二维码，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。简单操作即可星标⭐️医药速览，第一时间收到我们的推送①点击标题下方“医药速览”  ②至右上角“...”  ③点击“设为星标