Zelenectide pevedotin

编者按：如何将治疗性药物高效且特异性地递送至病灶组织，一直是新药研发的重要课题。偶联药物通过将能与目标组织中特异蛋白或受体结合的配体与治疗性载荷进行偶联，成为提升安全性与疗效的新策略。在常见的单克隆抗体之外，小分子、多肽、寡核苷酸等分子也可作为靶向配体，实现药物的精准递送。然而，这类偶联策略在提升靶向性的同时，也伴随着复杂的化学合成挑战。药明康德在化学业务上的丰富经验为开发这类新一代疗法打下坚实的基础，旗下WuXi TIDES全面的平台能力可为复杂的偶联药物提供一体化解决方案。本文将介绍2025年全球范围内偶联药物管线迎来的部分新进展。 偶联药物的核心结构包括三部分：用于识别靶点的配体、具有治疗活性的有效载荷，以及连接两者的连接子。与传统的被动靶向或全身暴露相比，偶联策略能够在分子层面“导航”药物，在提高疗效的同时显著降低毒性。 除了传统的抗体偶联药物（ADC），近年来采用小分子、多肽或寡核苷酸作为靶向配体的新一代偶联药物也在快速发展，其所搭载的有效载荷涵盖传统细胞毒性化合物、放射性同位素以及寡核苷酸等创新治疗手段，呈现出多样化趋势。 通过公开渠道梳理，全球范围内有上百款偶联药物管线处于积极的临床研究阶段，主要包括了抗体偶联药物（ADC）、放射性同位素偶联药物（RDC）、多肽偶联药物（PDC），此外还包括免疫刺激抗体偶联药物、抗体寡核苷酸偶联（AOC）、小分子偶联药物（SMDC）、抗体细胞偶联药物（ACC）等等，适应症涉及癌症、罕见病、自身免疫、代谢性疾病等等。2025年以来，这些不同类型的偶联药物研发管线均迎来新进展。 ADC领域，2025年多款创新ADC获得监管机构批准上市。比如，10月，美国FDA批准GSK靶向BCMA的ADC药物Blenrep，联合硼替佐米和地塞米松，用于治疗至少接受过两种既往疗法的复发或难治性多发性骨髓瘤成年患者。5月，FDA批准艾伯维（AbbVie）靶向c-Met的ADC药物Emrelis上市，用于治疗c-Met蛋白高度表达的局部晚期或转移性非鳞状非小细胞肺癌（NSCLC）成年患者。1月，阿斯利康与第一三共联合开发的靶向Trop2的ADC药物Datroway获批，用于治疗无法切除或转移性HR阳性、HER2阴性乳腺癌成人患者；该产品于6月再获FDA批准，用于治疗既往接受过EGFR靶向治疗和铂类化疗的局部晚期或转移性EGFR突变NSCLC成年患者。 RDC也是偶联药物的重要类型之一。这类药物通过将放射性同位素与靶向特定组织的配体偶联，将放射性物质精准递送到肿瘤组织，同时最大限度减少对健康组织的损害。公开资料显示，全球范围内已有数百款RDC新药管线进入临床研究阶段，靶向配体包括多肽、抗体、小分子等。 2025年以来，这一领域也迎来新药研发进展，比如：诺华的RDC疗法Pluvicto再次获得FDA批准，用于治疗PSMA阳性转移性去势抵抗性前列腺癌患者。这是一款将靶向PSMA的小分子化合物与放射性同位素（177Lu）连接在一起的放射性配体疗法。ITM Isotope Technologies开发的基于多肽偶联的靶向RDC疗法177Lu-edotreotide在3期临床试验中达到主要终点，FDA已经于今年11月受理该药的NDA申请，拟用于治疗胃肠胰神经内分泌肿瘤（GEP-NETs）。再如，Cellectar Biosciences开发的放射性偶联药物iopofosine I 131获得FDA授予的突破性疗法认定，用于治疗复发/难治性华氏巨球蛋白血症。该药物将磷酸酯与放射性同位素偶联，能够特异性结合癌细胞表面的特定脂质区域。Telix Pharmaceuticals于4月公布，其RDC药物TLX101（131I-iodofalan）在临床2期研究中，在治疗复发性高级别胶质瘤（HGG）患者时取得初步积极结果。TLX101为LAT-1靶向放射性同位素-小分子偶联药物，可自由通过血脑屏障进入大脑，并靶向胶质母细胞瘤过度表达的LAT-1精准辐射癌细胞并促使其凋亡，以达到治疗效果。 其他类型的PDC新药也迎来新进展。相比抗体，多肽具有分子量小、组织穿透能力强、易于化学合成等优势，成为新一代偶联药物研发的关键方向之一。比如，11月，Bicycle Therapeutics公司研发的双环肽偶联毒素在研疗法Zelenectide pevedotin (BT8009)在晚期实体瘤患者中的首次人体1/2期剂量递增和扩展研究结果公布。BT8009由一种高选择性靶向Nectin-4的双环肽与单甲基奥瑞他汀E连接而成。研究表明，该产品单药治疗显示出总体上耐受性良好的安全性特征和初步疗效，特别是在尿路上皮癌中。再如，同宜医药7月宣布，公司靶向叶酸受体（FRα）和TRPV6受体双靶偶联药物（Bi-XDC）新药CBP-1008（瑞可福泰）获中国NMPA同意开展铂耐药卵巢癌3期临床试验。CBP-1008为一款同时利用小分子叶酸配体/多肽TRPV6的双靶向偶联药物。 寡核苷酸药物近年来在多种疾病治疗中发挥重要作用。为突破传统寡核苷酸药物组织渗透性不足、肌肉细胞吸收效率有限等局限，行业正积极开发新一代偶联技术，比如通过将寡核苷酸与细胞穿透肽（CPP）或抗体片段结合，形成多肽-PMO偶联物（PPMO），以及抗体偶联寡核苷酸（AOC）等创新疗法。今年以来，这一领域也取得新进展。比如，3月，Avidity Biosciences公布其AOC疗法delpacibart zotadirsen在治疗杜氏肌营养不良症（DMD）的1/2期试验中展现出抗肌萎缩蛋白表达能力，该在研药物由靶向TfR1的单抗和促进编码抗肌萎缩蛋白的mRNA前体产生外显子44跳跃的寡核苷酸偶联而成。6月，Avidity Biosciences公司公布了其用于治疗面肩肱型肌营养不良症（FSHD）的在研AOC疗法delpacibart braxlosiran（del-brax）在临床1/2期试验中的积极新数据。该产品由一种专有的转铁蛋白受体1（TfR1）靶向单克隆抗体，与靶向DUX4 mRNA的siRNA偶联所组成。 2025年以来，多种不同类型的偶联药物研发管线还迎来其他一系列新进展，限于篇幅，此处不一一列举。 一体化平台赋能偶联药物开发 通过合理匹配载荷类型与释放机制，偶联药物能够实现在靶点组织的高效积聚与精准杀伤，为多种难治性疾病提供了新的治疗方向。然而，此类疗法复杂的化学合成过程也给其开发带来了重大挑战。 药明康德在化学业务上的丰富经验为开发偶联药物打下坚实的基础。药明康德旗下WuXi TIDES搭建了独特的CRDMO平台，为全球合作伙伴开发寡核苷酸、多肽药物及相关化学偶联物（TIDES药物）提供高效、灵活和高质量解决方案。 比如，在多肽偶联药物开发方面，WuXi TIDES全面的多肽平台结合了小分子化学能力，支持多肽-毒素、多肽-金属、多肽-GalNAc、多肽-寡核苷酸和放射性核素偶联药物等偶联药物的开发。WuXi TIDES的一体化平台让多个团队能够并行攻关，密切合作，显著提高项目推进速度。 WuXi TIDES同样可以为复杂的寡核苷酸偶联药物提供一站式解决方案，支持从药物发现到CMC开发再到商业化⽣产。平台能力支持寡核苷酸与GalNAc、多肽、适配体、脂质、药物和其它定制小分子的偶联。 未来，WuXi TIDES将继续依托其一体化、端到端的CRDMO平台，支持合作伙伴推进包括多肽偶联药物、寡核苷酸偶联药物在内的多类偶联药物研发，助力前沿科技转化为惠及全球患者的突破性疗法。 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号回复“转载”，获取转载须知。

CAMBRIDGE, England & BOSTON--(BUSINESS WIRE)--Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle®) technology, today announced it has entered into a 15-year contract including an option to renew with the UK Nuclear Decommissioning Authority (NDA) for access to up to 400 tonnes of reprocessed uranium (RepU). RepU continually regenerates providing a potentially sustainable supply of 212Pb. Bicycle intends to utilize the RepU provided by this agreement in its development of potential lifesaving therapies. In addition, Bicycle announced a collaboration with United Kingdom National Nuclear Laboratory (UKNNL), pursuant to which it plans to extract 228Th from the RepU obtained from NDA. The extracted 228Th will then be further processed into 224Ra and loaded into a bespoke 212Pb generator being developed exclusively for Bicycle by SpectronRx. 212Pb is a radioisotope and one of the more potent therapeutic payloads against cancer cells known as Targeted Alpha Therapy (TAT). Collectively, this bespoke set of arrangements is designed to support the potential discovery, development, and commercial supply of a portfolio of Bicycle® Radioconjugates (BRC®) containing 212Pb. “Cancer is a disease that affects millions worldwide, and tears too many families apart. Breakthroughs in medical science are giving more cancer patients and their loved ones hope, and this unique partnership could help take that work even further. Turning nuclear material into cutting-edge cancer treatments sounds like science fiction – but thanks to the brilliance of scientists, researchers and doctors, it could be a life-saving reality. Work like this shows exactly why we’re determined to support our life sciences innovators to make groundbreaking new treatments possible,” said Liz Kendall, Secretary of State. “These new collaborations are testaments to the potential of Bicycle to advance a differentiated and exciting isotope agnostic radiopharmaceuticals portfolio. We believe we now have the resources and infrastructure we need to create the world’s first end-to-end 212Pb radiopharmaceutical ecosystem from discovery through development to commercial supply. We believe the potential of BRCs and our ability to incorporate the appropriate isotopes for specific patient needs is unique and creates significant value-creating capabilities,” said Mike Hannay, D.Sc., FRPharmS, chief product and supply chain officer of Bicycle Therapeutics. “We are incredibly grateful to the UK government for their recognition of Bicycle’s potential to develop BRCs with a 15-year access agreement for reprocessed uranium, and to our partners SpectronRx with whom we are developing a bespoke 212Pb generator. We look forward to advancing these dynamic collaborations and developing our pipeline of radiopharmaceuticals with the potential of improving lives for cancer patients around the globe.” “I am delighted with the progress we are making in establishing ourselves as a potential leader in radiopharmaceutical R&D. Today’s announcement builds on our previous announcements concerning our agreement with Eckert & Ziegler to supply a range of radioisotopes for the manufacture of BRC products as well as the formation of our Research and Innovation Advisory Board (RAB) comprising some of the worlds most esteemed experts in radiopharmaceuticals,” said Bicycle Therapeutics CEO Kevin Lee, Ph.D. “As we continue to advance our emerging BRC pipeline, currently with novel targets EphA2 and MT1-MMP, we look forward to presenting initial EphA2 human imaging data in the first half of 2026 and initiating our own Bicycle study in 2026.” About Bicycle Therapeutics Bicycle Therapeutics is a clinical-stage pharmaceutical company developing a novel class of medicines, referred to as Bicycle® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycle molecules attractive candidates for drug development. The company is evaluating zelenectide pevedotin (formerly BT8009), a Bicycle® Drug Conjugate (BDC®) targeting Nectin-4, a well-validated tumor antigen; BT5528, a BDC molecule targeting EphA2, a historically undruggable target; and BT7480, a Bicycle Tumor-Targeted Immune Cell Agonist® (Bicycle TICA®) targeting Nectin-4 and agonizing CD137, in company-sponsored clinical trials. Additionally, the company is developing Bicycle® Radioconjugates (BRC®) for radiopharmaceutical use and, through various partnerships, is exploring the use of Bicycle® technology to develop therapies for diseases beyond oncology. Bicycle Therapeutics is headquartered in Cambridge, UK, with many key functions and members of its leadership team located in Cambridge, Mass. For more information, visit bicycletherapeutics.com. Forward Looking Statements This press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding: Bicycle’s expectations with respect to the benefits of its agreements and collaborations with NDA, UKNNL, and SpectronRx, respectively; Bicycle’s ability to advance a differentiated and exciting isotope agnostic radiopharmaceuticals portfolio; Bicycle’s ability to leverage its agreements with NDA and SpectronRx and collaboration with UKNNL to create the world’s first end-to-end 212Pb radiopharmaceutical ecosystem; Bicycle’s ability to incorporate the appropriate isotopes for specific patient needs to support significant value-creating capabilities; the initiation of new clinical trials, the progress of Bicycle’s clinical trials, reporting data from Bicycle’s clinical trials and the timing of EphA2 human imaging data; the development of BRC molecules for radiopharmaceutical use; and the use of Bicycle Therapeutics’ technology through various partnerships to develop therapies for diseases beyond oncology. Bicycle Therapeutics may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in research and development and in the initiation, progress and completion of clinical trials and clinical development of Bicycle Therapeutics’ product candidates; the risk that Bicycle may not realize the intended benefits of its technology or partnerships; the risk that Bicycle may not achieve any of its clinical development strategies; timing of results from clinical trials; whether the outcomes of preclinical studies and prior clinical trials will be predictive of future clinical trial results; the risk that trials may have unsatisfactory outcomes; potential adverse effects arising from the testing or use of Bicycle’s product candidates; and other important factors, any of which could cause Bicycle Therapeutics’ actual results to differ from those contained in the forward-looking statements, are described in greater detail in the section entitled “Risk Factors” in Bicycle Therapeutics’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on October 30, 2025, as well as in other filings Bicycle Therapeutics may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Bicycle Therapeutics expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law.