Docetaxel

//   如何在不破坏整体免疫平衡的前提下，精准清除肿瘤微环境中的Treg细胞，成为新一代免疫治疗的重要突破方向。 撰文|徐卉（作者系相关领域研究人员） 当地时间10月6日，瑞典卡罗琳医学院宣布，将2025年诺贝尔生理学或医学奖颁给Mary E. Brunkow、Fred Ramsdell 和坂口志文，以表彰他们在外周免疫耐受方面的研究贡献。 图片来源|公开资料  他们在外周免疫耐受领域的开创性发现，成功鉴定出调节性T细胞，并揭示了免疫系统如何被调控以防止自我攻击。他们的发现为新研究领域奠定了基础，并推动了新疗法的发展，例如癌症和自身免疫性疾病的治疗。 调节性T细胞和肿瘤治疗 T细胞是免疫系统中的重要淋巴细胞群，其主要包括效应T细胞（effector T cells，Teffs）和调节性T细胞（regulatory T cells，Tregs）两类。其中，Tregs在维持对自身耐受方面发挥着关键作用，其核心功能是抑制过度的免疫反应，有效防止过度炎症和自身免疫反应的发生。 简单来说，Teffs是油门，而Tregs是刹车。当免疫系统需要对病原体发动攻击时，油门被踩下；当威胁解除时，Tregs会及时介入，防止免疫系统继续过度活跃，避免“误伤”自身组织。 图片来源|公开资料 Treg细胞也在肿瘤免疫逃逸中扮演着特殊角色。它们原本是维持免疫耐受、防止自身免疫反应的重要细胞，但是在肿瘤微环境中常被“招安”，成为癌细胞的保护伞。 Treg细胞通过分泌免疫抑制性因子（如IL-10、TGF-β）和表达CTLA-4等分子，抑制效应T细胞的活化和攻击功能，从而帮助肿瘤逃避免疫清除。研究发现，肿瘤微环境（tumor microenvironment，TME）中Tregs的大量存在与多种癌症患者的预后不良、转移增加、对免疫治疗的反应降低以及复发率较高呈正相关。 所以，靶向Treg细胞可能是治疗肿瘤的有效策略。 Treg细胞表面高表达CTLA-4，而全球首款CTLA-4抑制剂伊匹木单抗（ipilimumab）于2011年获批上市，证实了通过解除免疫刹车治疗癌症的可行性。 图片来源|公开资料 但是ipilimumab存在严重的毒性问题，究其原因，是因为无法区分肿瘤微环境中的Treg和健康组织中的Treg，导致全身性免疫过度激活，引发严重的自身免疫样毒性。 ipilimumab的这种“杀敌一千，自损八百”的模式，使得医生往往需要在疗效和毒性之间艰难权衡。因此在多款获批治疗方案中，均需与其他药物联用，甚至被视为联合用药的“配角”，限制了其在肿瘤治疗中的广泛应用。 如何在不破坏整体免疫平衡的前提下，精准清除肿瘤微环境中的Treg细胞，成为新一代免疫治疗的重要突破方向。 ONC-392的科学逻辑 知名免疫学学家刘阳和郑盼团队的研究发现，CTLA-4抗体发挥作用，是通过强ADCC（抗体依赖的细胞介导效应）来清除肿瘤局部高表达CTLA-4的Treg细胞，从而降低Treg对杀伤性T细胞的抑制；而副作用是由于抗体与CTLA-4的结合体在内吞后被溶酶体清除，导致细胞表面CTLA-4大量减少引发自免反应。 他们创立OncoC4公司，开发了新一代、pH敏感的CTLA-4抗体药物ONC-392。它的创新设计旨在实现“增效减毒”：1）利用pH敏感的特性，避免CTLA-4在细胞内溶酶体的降解，大幅提升治疗窗口；2）结合Fc段的工程化改造，更有效、精准地清除肿瘤微环境中的调节性T细胞，从而实现更优的抗肿瘤效果。 图片来源|公开资料 ONC-392在正常组织/器官和肿瘤微环境的典型pH值下，能够与CTLA-4结合并相互作用。当pH值下降到6.0以下时，ONC-392迅速与其靶蛋白分离，从而使CTLA-4分子维持其正常的生命周期，避免抗体诱导的溶酶体降解。 基于此，正常组织中Treg细胞表面的CTLA可以维持正常，减少了免疫副反应，提高了ONC-392的治疗指数。同时，也保留了肿瘤微环境中Treg表面的靶蛋白，ONC-392便通过更强的ADCC/ADCP效应耗竭这些肿瘤浸润的Treg。 这一独特的功能不仅降低了毒性，而且提高了疗效，从而获得了更好的治疗指数，允许其提升至足够的剂量来释放抗CTLA-4抗体的免疫治疗潜力。 图片来源|公开资料 ONC-392的研发进展 2019年12月，ONC-392的IND申请获得美国FDA批准； 2020年8月，ONC-392的IND申请获得中国NMPA批准； 2021年11月，ONC-392的1a期临床试验结果发布； 2023年3月，OncoC4与BioNTech达成战略合作协议，共同开发OncoC4的下一代抗CTLA-4抗体候选物gotistobart（BNT316/ONC-392），OncoC4获得2亿美元预付款，及未公开的里程碑付款和两位数的分级特许权使用费； 2023年6月，ONC-392治疗PD-(L)1耐药性NSCLC的1/2期临床试验结果发布，并启动3期临床试验PRESERVE-003。 图片来源|公开资料 PRESERVE-003是一项随机、开放标签、活性对照、多中心3期临床研究（NCT 05671510），分为两个阶段： 第一阶段，即剂量确认阶段，旨在评估在鳞状和非鳞状非小细胞肺癌（NSCLC）患者中，与多西他赛相比，两种gotistobart给药方案（低剂量和高剂量）的有效性和安全性。根据公司官网的披露，第一阶段已经完成，数据支持第二阶段选择高剂量治疗。 第二阶段，旨在评估gotistobart高剂量与多西他赛相比，治疗鳞状细胞非小细胞肺癌的安全性和有效性。研究主要终点是总生存期（OS）。 图片来源|公开资料 2024年10月，美国FDA曾暂停过PRESERVE-003研究，但是很快在12月即批准继续进行。暂停的原因系独立数据监测委员会发现鳞状和非鳞状疾病患者之间的“不同结果”。恢复开展临床试验后，只招募鳞状NSCLC患者。 据OncoC4公司官网披露，目前第二阶段的入组进展顺利，全球已有160个临床机构参与。 图片来源|公开资料  全新的探索：与核药Lu177的联用 值得注意的是，gotistobart（BNT316/ONC-392）还有一项处于“正在招募”状态的临床试验——联合诺华的核药Lu 177治疗转移性去势抵抗性前列腺癌（mCRPC）患者。这展示了一个全新的探索方向。 图片来源|公开资料  Lu 177为什么需要和其它药物联用呢？ 该研究的PI、纽约大学肿瘤内科医生David Wise博士在访谈中表示，Lu的治疗耐久性实际上与多西紫杉醇的耐久性没有太大区别。一旦患者完成治疗，疾病往往会进展，患者会非常崩溃。因此，需要做些什么来延长治疗的持久性。 为了弄清楚这个问题，Treg细胞受到关注。研究表明，效应T细胞会被辐射耗尽，而Treg细胞则不会。于是科学家们尝试寻找能够耗竭肿瘤微环境中Treg细胞的疗法，并且和OncoC4公司达成临床试验合作。 PRESERVE-006（NCT05682443）是一项开放标签、随机、主动对照、多中心的1/2期临床试验，旨在研究Gotistobart联合Lu 177治疗雄激素受体通路抑制后进展的mCRPC患者。 图片来源|公开资料 David Wise博士在ASCO 2025的演讲结束时，讨论gotistobart（BNT316/ONC-392）联合Lu 177治疗mCRPC患者的1期研究，得出以下要点： • 总体研究结果支持gotistobart剂量低于10mg/kg的联合方案 • 与单独使用Lu 177相比，gotistobart + Lu 177的联用治疗耐受性良好，并且与每4周3mg/kg 和每6周6mg/kg的剂量下具有持久的PSA50反应，支持这些剂量用于正在进行的2期临床试验 • 2期试验预计将于2025年底完成入组 1期研究结果已经发布于ASCO 2025，参考链接： https://www.urotoday.com/conference-highlights/asco-2025/asco-2025-prostate-cancer/160813-asco-2025-preserve-006-phase-1-study-of-gotistobart-bnt316-onc-392-in-combination-with-lutetium-lu-177-vipivotide-tetraxetan-in-patients-with-mcrpc.html  https://www.urotoday.com/video-lectures/advanced-prostate-cancer/video/mediaitem/4879-phase-i-trial-combines-onc-392-with-lutetium-177-for-prostate-cancer-david-wise.html  总结 2025年诺贝尔生理学或医学奖再次将焦点聚向免疫调控与Treg细胞，这不仅是对基础科学的致敬，也让我们重新思考CTLA-4这一经典靶点在肿瘤免疫中的发展方向。 ipilimumab证明了“解除免疫刹车”能够带来持久临床获益，同时也揭示了系统性免疫激活的风险。在此基础上，ONC-392以“选择性调节Tregs”的新策略，探索在保留免疫耐受的同时精准激活抗肿瘤免疫的可能，为CTLA-4抗体开辟了新的发展方向。它所代表的，不只是机制上的创新，更是免疫治疗向更精准、更平衡、更可持续发展的未来迈出的关键一步。 （作者观点不代表研发客立场） 总第2601期 访问研发客网站可浏览更多文章 www.PharmaDJ.com

Dr. Kates’ experience as chair of the landmark Phase 3 BRIDGE bladder cancer trial and dedication to patient care will be invaluable to the NDV-01 Phase 3 program Phase 3 program for NDV-01 expected to begin in H1 2026 CORAL GABLES, Fla., Oct. 07, 2025 (GLOBE NEWSWIRE) -- Relmada Therapeutics, Inc. (Nasdaq: RLMD, “Relmada” or the “Company”), a clinical-stage biotechnology company advancing innovative therapies for oncology and central nervous system indications, today announced the appointment of Max Kates, MD, Associate Professor of Urology and Oncology at Johns Hopkins University School of Medicine, to Relmada’s Clinical Advisory Board (CAB) to support the development of NDV-01 for the potential treatment of non-muscle invasive bladder cancer (NMIBC). Relmada intends to initiate the Phase 3 program for NDV-01 in H1 2026. “With preparations actively underway for the Phase 3 NDV-01 clinical program in NMIBC, we are very pleased to welcome Dr. Kates to the Relmada Clinical Advisory Board. We believe that Max’s experience chairing the landmark Phase 3 BRIDGE trial and leading several other practice-changing studies gives him a unique clinical perspective that will be invaluable to the design and conduct of the Phase 3 program,” said Raj Pruthi, MD, Chief Medical Officer-Urology, Relmada. “In addition, Max’s first-hand knowledge of the operational complexities inherent to a high-volume urologic oncology practice will help us to strengthen the Phase 3 program for NDV-01 and ensure its real-world applicability.” “As the chair of the international Phase 3 Bridge Study, I have gained a deep appreciation for the clinical community’s optimism for the intravesicular delivery of gemcitabine and docetaxel as a potential bladder sparing treatment for NMIBC,” said Dr. Kates. “The initial safety and efficacy data for NDV-01, presented at the American Urologic Association in April, 2025, and updated in August, underscore the significant benefit that a sustained release formulation of “Gem/Doce” could offer urologic oncology practices and bladder cancer patients. I believe NDV-01 has the potential to transform the treatment of NMIBC and I am pleased to join the Relmada Clinical Advisory Board and eager to contribute my expertise to the pivotal program.” About Max Kates, MDDr. Kates is a nationally recognized clinician-scientist in bladder cancer with one of the largest surgical bladder cancer practices in the U.S., integrating clinical care with translational research. Dr. Kates serves as chair of the Phase 3 EA8212 BRIDGE Trial (NCT05538663) trial, comparing Gemcitabine/Docetaxel to BCG (Bacillus Calmette-Guérin) in non–muscle invasive bladder cancer (over 900 patients enrolled across >65 centers). He has also been the Principal Investigator on numerous studies evaluating new potential treatments for NMIBC. Dr. Kates has pioneered improvements in surgical innovation for robotic intracorporeal cystectomy and neobladder as well as novel techniques and early recovery programs for TURBT translational research, has advanced understanding of immune resistance in BCG-unresponsive disease, pioneered novel intravesical therapies, and explored antibody–drug conjugates and immunotherapy for bladder preservation. Throughout his career, Dr. Kates has published more than 150 peer-reviewed manuscripts in leading journals such as Clinical Cancer Research, Cancer Immunology Research, Journal of Urology, and European Urology. Dr. Kates also serves as a reviewer for prominent journals including the New England Journal of Medicine, and the Journal of Clinical Oncology. Dr. Kates is the R. Christian B. Evensen Professor of Urology and Director of the Division of Urologic Oncology at Johns Hopkins Hospital, and Associate Professor, Urology and Oncology and Co-Director of the Greenberg Bladder Cancer Institute. He received his medical degree from Mount Sinai School of Medicine in New York. He trained in general surgery and urologic surgery at John Hopkins Hospital in Baltimore, Maryland and completed a Clinical Research Fellowship at Columbia University College of Physicians and Surgeons in New York. Dr. Kates graduated with High Distinction with a B.A. from Wesleyan University. About NDV-01NDV-01 is a sustained-release, intravesical formulation of gemcitabine and docetaxel (Gem/Doce), in development for the treatment of non-muscle invasive bladder cancer. It is designed to enable Gem/Doce bladder retention and gradual drug release over 10 days. The formulation creates a soft matrix that enhances local exposure while minimizing systemic toxicity. NDV-01 is convenient to administer in-office, in less than 10 minutes, and does not require anesthesia or specialized equipment. It is protected by patents through 2038. About NMIBCNMIBC represents 75-80% of all bladder cancer cases and is associated with high recurrence (50 –80% over 5 years). With over 744,000 prevalent cases in the U.S. and limited treatment options, the market opportunity is significant. NDV-01 has the potential to serve as a frontline or salvage therapy and could be applicable across multiple NMIBC subtypes. About Relmada Therapeutics, Inc.Relmada Therapeutics is a clinical-stage biotechnology company focused on developing transformative therapies for oncology-related and central nervous system conditions. Its lead candidates, NDV-01 and sepranolone, are advancing through mid-stage clinical development with the potential to address significant unmet needs. For more information, visit www.relmada.com Forward-Looking Statements: The Private Securities Litigation Reform Act of 1995 provides a safe harbor for forward-looking statements made by us or on our behalf. This press release contains statements which constitute “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Any statement that is not historical in nature is a forward-looking statement and may be identified by the use of words and phrases such as “if”, “may”, “expects”, “anticipates”, “believes”, “will”, “will likely result”, “will continue”, “plans to”, “potential”, “promising”, and similar expressions. These statements are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements, including the potential for Relmada’s product candidates to progress, including the potential for Phase 2 NDV-01 data to continue to deliver positive results supporting further development, potential for clinical trials to deliver statistically and/or clinically significant evidence of efficacy and/or safety, failure of top-line results to accurately reflect the complete results of the trial, failure of planned or ongoing preclinical and clinical studies to demonstrate expected results, potential failure to secure FDA agreement on the regulatory path for NDV-01, and sepranolone, or that future NDV-01, or sepranolone, clinical results will be acceptable to the FDA, failure to secure adequate NDV-01, or sepranolone, drug supply, and the other risk factors described under the heading “Risk Factors” set forth in the Company’s reports filed with the SEC from time to time. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Relmada undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Readers are cautioned that it is not possible to predict or identify all the risks, uncertainties and other factors that may affect future results and that the risks described herein should not be a complete list. Investor Contact:Brian RitchieLifeSci Advisorsbritchie@lifesciadvisors.com Media Inquiries:Corporate Communicationsmedia@relmada.com