Venetoclax

编者按：20世纪中叶，科学界对白血病几乎没有有效的控制策略。由于当时的治疗手段非常有限，患者在诊断后不久便不幸去世，白血病的诊断往往代表着“死刑”。从20世纪的同种异体骨髓移植手术到本世纪不断涌现的靶向疗法，科学界的持续探索为白血病患者打开了通往治愈的大门。长期以来，药明康德也在支持全球合作伙伴从药物研究（R）、开发（D）到商业化生产（M）各个阶段的需求，通过独特的一体化、端到端CRDMO模式，助力多款白血病新疗法问世，造福全球患者。值此世界白血病日，本文将回顾由科学铺设的白血病治疗之路。 “骨髓移植之父”的拯救之路 白血病由骨髓产生过多异常白细胞而引发，并且会抑制正常细胞的发育，导致红细胞无法将氧气输送到全身。那时，科学界曾出现了一些较为“超前”的想法：用骨髓移植来帮助产生全新的健康血细胞。不过在当时，动物模型的表现普遍不太理想，接受移植的受体会排斥移植的骨髓，并且这些骨髓难以长时间存活进而发挥治疗效果。一些声音认为，这条路注定走不通，相关研究也一度进展缓慢。 20世纪30年代，在美国得克萨斯大学读书的Donnall Thomas正在为生活费所奔波。为了能维持学业和日常开销，Donnall做了许多兼职工作，包括在宿舍的前台进行接待。此时的他还不知道自己将在未来改变白血病治疗领域格局，更不用说“骨髓移植之父”的称号以及诺贝尔奖。 ▲Donnall Thomas因“在器官或细胞移植方面治疗疾病作出的贡献”获得了1990年的诺贝尔生理学或医学奖（图片来源：参考资料[1]，Nobel Foundation archive） 在后来的自传中，他特别提到了与妻子相遇的那个日子——那天，得克萨斯州罕见地下了雪。Donnall在刚准备进入宿舍时，被一个雪球砸中了脸，他循着雪球方向找到了一名女生。就这样，他认识了Dottie Martin。在之后的生涯中，Dottie不仅是妻子，更是成为了Donnall的得力助手。当Donnall毕业进入哈佛医学院，Dottie就辞去了自己的新闻业工作，并毅然加入医学院参加了实验室技术员培训，之后夫妻两人一直一起开展研究工作。 Donnall于1946年在哈佛完成住院医生训练，此后先后进入西雅图和波士顿的多家医院工作。他亲眼见证了许多白血病患者与家属在病痛面前的绝望。这些经历使他逐渐意识到，传统手段几乎无法为这类病人带来真正希望。他联想到，有研究者发现保护脾脏可以让小鼠免受致命辐射的伤害，通过骨髓输注也可以获得类似的保护效果。这些结果实际都指向了一个方向，那就是活骨髓细胞具有保护辐射、重构造血系统的作用。 于是，Donnall有了一个大胆的假设：能否通过移植健康的骨髓来替代患者病变的造血系统？他建立了一个小型实验室，利用动物模型进行了骨髓移植实验。Dottie负责做放疗、护理和观察，并仔细记录数据。这些实验让他们掌握了骨髓移植的关键技巧。 随后，Donnall找到了数名病情危重的白血病患者，他们几乎已经没有其他治疗选择。患者在接受放疗清除原本的造血系统后，接受了近亲的骨髓移植。这是医学史上的首次尝试，也代表着白血病治疗的一个全新里程碑。1957年，Donnall将这些结果发表在《新英格兰医学杂志》上后，立即引起了全球医学界的高度关注。不过，其他学者仍花费了十多年才逐渐接受和认可了这一技术的价值。 从“死刑”宣判到治愈希望 在这一过程中，Donnall并没有因外界的质疑而停下脚步。他加入了弗雷德·哈钦森癌症研究中心（Fred Hutchinson Cancer Research Center），成为该中心的创始成员之一。在骨髓移植早期，最棘手的问题就是免疫排斥。而随着人类白细胞抗原（HLA）系统的发现与应用，科学家逐渐认识到，如果供者和受者的 HLA 类型差异过大，移植就几乎必然失败；反之，如果供受双方的 HLA 高度相似甚至完全匹配，移植的成功率就会显著提高。 Donnall在后续的骨髓移植试验中，提前进行了HLA配型筛选。他还研究了另一种抗免疫排斥药物甲氨蝶呤，成功降低了“移植物抗宿主反应”发生率。此外，Donnall还发现当白血病患者接受同卵双胞胎的移植后，他们的病情往往在移植后短短几个月内复发。但是，接受与自身略有不同的细胞（例如来自基因不完全匹配的兄弟姐妹，甚至是无血缘关系的捐赠者）的患者，复发率要低得多。 这些发现为后续的骨髓移植的成功发展和普及奠定了重要基础。在上世纪70年代末，骨髓移植刚刚出现在公众视野中的时候，全球每年仅仅只有数百例移植手术。仅过了不到10年，这一数字就增长了约10倍。在过去，白血病的诊断意味着很快就会去世。而随着骨髓移植的普及，部分白血病类型，例如儿童急性淋巴细胞性白血病（ALL）的五年生存率可提升至90%。 1990年10月的一个凌晨，一道电话铃声将Donnall从睡梦中吵醒。他接起电话——是一名记者想向他采访获得诺贝尔奖的感受。他还以为是哪位同事的恶作剧，半信半疑的Dottie也让他赶紧应付两句，挂掉电话继续睡觉。但随后，电话开始响个不停，更多的记者打了过来，他这才相信自己获得了当年的诺贝尔生理学或医学奖。待颁奖典礼时，Donnall与Dottie一同前往了瑞典斯德哥尔摩。在演讲中，Donnall看向Dottie，“如果没有Dottie，我可能做不到这一切。” 图片来源：123RF 获奖后，Donnall将奖金全部捐赠给了弗雷德·哈钦森癌症研究中心，助力更多后续研究的开展。这里的研究者仍在继续探索更多拯救白血病的治疗策略，例如后续发展的血液干细胞移植已用于治疗多种白血病和淋巴瘤，扩大移植受益群体的范围；减轻强度的移植术，使身体较弱的患者也能接受移植。 另外，研究者通过能够精确识别肿瘤的免疫分子，或改造出的能够直接靶向并摧毁癌细胞的杀伤性T细胞来清除肿瘤。基于数十年在白血病领域分子机制的探索，研究团队还在积极与其他团队合作，研究耐药机制和与免疫疗法结合的策略，寻找可用的小分子抑制剂。这也推动了更多救命策略的诞生。 新疗法改写白血病治疗格局 在Donnall等人前期工作成果的基础上，近年来多种白血病疗法陆续涌现，已经挽救了大量患者的生命。以一种常见的白血病亚型——慢性淋巴细胞白血病（CLL）为例，造血干细胞移植为患者提供了治愈的手段，而对于因为身体状况、缺乏合适供者而无法接受移植的CLL患者，近年来多款不同类型的获批药物为他们实现了疾病的控制。 进入21世纪以来，美国FDA已经批准了至少14款治疗CLL的新疗法，一个重要转变是靶向疗法的兴起。例如，布鲁顿氏酪氨酸激酶（BTK）在CLL的癌细胞中表达升高，成为CLL治疗的重要靶点。BTK抑制剂伊布替尼（ibrutinib）在2013年获批用于套细胞淋巴瘤治疗后，又在2014年获批用于CLL的治疗。后续随访结果显示，伊布替尼治疗CLL的总缓解率达到88%。此外，已获FDA批准的BTK抑制剂还包括泽布替尼（zanubrutinib）、首个非共价BTK抑制剂匹妥布替尼（pirtobrutinib）、阿可替尼（acalabrutinib）。 图片来源：123RF PI3K是另一种在B细胞恶性肿瘤中过度表达的蛋白，PI3K-δ抑制剂艾代拉利司（idelalisib）和PI3K-δ、PI3K-γ双重抑制剂度恩西布（duvelisib）相继获批，用于治疗复发/难治性CLL。维奈克拉（venetoclax）则是一种BCL-2抑制剂，通过选择性抑制B细胞淋巴瘤因子-2（BCL-2）的功能，促进癌细胞凋亡。 以CD20等抗原为靶点的单克隆抗体，是CLL靶向治疗的另一个重要方向。于20世纪末问世的利妥昔单抗（rituximab）是一款靶向CD20的单抗，其新适应症在2010年获FDA批准，与其他药物联合使用，治疗CD20阳性CLL患者。此外，已经获批用于治疗CLL的CD20单抗还包括奥法妥木单抗（ofatumumab）、奥妥珠单抗（obinutuzumab）；阿仑珠单抗（alemtuzumab）则是一款靶向CD52的单抗药物。 除上述药物之外，近年来获批的CLL疗法还有化疗药物苯达莫司汀（bendamustine），以及2024年获批的靶向CD19的CAR-T细胞疗法lisocabtagene maraleucel（liso-cel）。 药明康德很高兴能为其中多款疗法提供赋能、助力合作伙伴的这些创新疗法来到全球患者身边。 这些获批药物在很大程度上改善了CLL患者的生活质量、延长了患者寿命，但科学与产业界的创新脚步仍未停下。当下还有近200款针对CLL的新疗法正处于积极的临床研究中，有望在未来造福更多患者。其中，多款药物已进入3期临床阶段，涵盖小分子靶向药和靶向蛋白降解剂等多种类型。 作为全球医药创新的赋能者，长期以来，药明康德都在支持全球合作伙伴从药物研究（R）、开发（D）到商业化生产（M）各个阶段的需求，通过独特的一体化、端到端CRDMO模式，助力突破性疗法研发。药明康德也将与业界同仁携手同行，共同推动白血病治疗的未来发展。 参考资料： [1] E. Donnall Thomas, Biographical. Retrieved September 2, 2025 from https://www.nobelprize.org/prizes/medicine/1990/thomas/biographical/ [2] Remembering E. Donnall Thomas. Retrieved September 2, 2025 from https://www.fredhutch.org/en/news/center-news/2012/10/e-donnall-thomas-obituary.html [3] A pioneering procedure’s expanding influence. Retrieved September 2, 2025 from https://www.fredhutch.org/en/news/center-news/2015/08/bone-marrow-transplant-influence.html [4] E. Donnall Thomas. Retrieved September 2, 2025 from https://www.washington.edu/alumni/columns/march98/thomas.html 欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。 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。 更多推荐 点个“在看”再走吧~

New candidates, APVO452 and APVO451, harness proprietary ADAPTIR-FLEXTM design to target prostate and multiple solid tumor cancers by simultaneously engaging tumor antigens, T cells, and immunosuppressive cells Mipletamig-driven clinical validation of the CRIS-7-derived CD3 binding domain underpins Aptevo's introduction of new, trispecific CD3-directed anti-cancer molecules SEATTLE, WASHINGTON / ACCESS Newswire / September 4, 2025 / Aptevo Therapeutics Inc. ("Aptevo" or the "Company") (NASDAQ:APVO), a clinical-stage biotechnology company focused on developing novel immuno-oncology therapeutics based on its proprietary ADAPTIRTMand ADAPTIR-FLEXTM platform technologies, today announced expansion of its anti-cancer pipeline with the filing of two provisional patents for trispecific candidates, APVO452 and APVO451 for prostate cancer and multiple, additional solid tumor types with significant unmet needs. These programs build on the Company's growing suite of CRIS-7-derived, CD3-directed molecules and are supported by compelling clinical validation from lead candidate, mipletamig, which has demonstrated strong clinical safety and efficacy for the treatment of acute myeloid leukemia (AML). A New Generation of CD3 Therapies Aptevo's CD3-engaging portfolio is anchored by mipletamig, a first-in-class CD123 x CD3 bispecific currently being evaluated in RAINIER, a Phase 1b/2 trial for frontline AML. In total, mipletamig has been evaluated in more than 100 patients across three trials, where mipletamig has consistently demonstrated high remission rates and a favorable safety and tolerability profile, with no observed cytokine release syndrome in frontline patients treated to date. Building on this clinical validation, Aptevo previously expanded the suite with tumor-directed bispecifics APVO442 (prostate, PSMA x CD3) and APVO455 (solid tumors, Nectin-4 x CD3). All share the CRIS-7-derived CD3 binding domain, designed to deliver tumor-specific immune activation with a lower risk of systemic toxicity. "It's thrilling to introduce Aptevo's first two trispecific immune cell engager biologics-and an exciting milestone for our team. Powered by our ADAPTIR-FLEX platform, these molecules are designed with a finely tuned mechanism of action that not only activates T cells in a tumor-specific manner but also modulates the immunosuppressive tumor microenvironment. This achievement reflects the monumental effort and exceptional talent of our highly capable team. Ultimately, we are creating therapeutics with the potential to fight cancer using multiple approaches of attack, but with a single molecule," said Peter Pavlik, PhD, Senior Director of Protein Engineering at Aptevo. Trispecifics Designed to Modulate the Tumor Microenvironment Expansion into trispecific molecule development represents a potentially profound emerging treatment option with the potential to unlock deeper, more durable anti-tumor responses by simultaneously engaging multiple immune pathways while limiting systemic toxicity. Solid tumors remain difficult to treat because the tumor microenvironment (TME) actively suppresses immune responses, limiting the efficacy of current therapies. To address this, Aptevo is advancing a new class of trispecific engagers that unite tumor targeting, T cell activation, and immune costimulation in a single molecule. This design has the potential to be delivered safely while harnessing the body's own immune system to fight tumors locally in the tumor microenvironment. APVO452 targeting PSMA, CD3, and CD40, is designed to address prostate cancers via PSMA targeting. This molecule works like a three-in-one tool: One-part locks onto the tumor, another part activates the body's T cells to fight, and the third part reprograms other immune cells that normally protect the tumor. In preclinical studies, this trispecific approach was able to effectively kill tumor cells and, importantly, only switched on the immune system when tumor cells were present APVO451 similarly incorporates trispecific design principles, targeting Nectin-4, CD3, and CD40, and is intended for a broad range of solid tumors. Early data indicate potent, anti-cancer activity that attacks cancer in multiple ways, increasing the opportunity to address critical unmet needs by offering treatment options for multiple solid tumors APVO452 targeting PSMA, CD3, and CD40, is designed to address prostate cancers via PSMA targeting. This molecule works like a three-in-one tool: One-part locks onto the tumor, another part activates the body's T cells to fight, and the third part reprograms other immune cells that normally protect the tumor. In preclinical studies, this trispecific approach was able to effectively kill tumor cells and, importantly, only switched on the immune system when tumor cells were present APVO451 similarly incorporates trispecific design principles, targeting Nectin-4, CD3, and CD40, and is intended for a broad range of solid tumors. Early data indicate potent, anti-cancer activity that attacks cancer in multiple ways, increasing the opportunity to address critical unmet needs by offering treatment options for multiple solid tumors "Beyond ramping up immune cell activity, there is a need for cancer treatments that achieve the true goal of immunotherapy in oncology: to restore balance to the immune system so it can kill tumor cells, while avoiding dangerous side effects. Tumor cells don't exist in isolation. There is a complex tumor environment that includes other types of cells and structures-that signal to each other, increasing tumor growth and progression, and suppressing the body from fighting back. It's not one single barrier; it's a whole network of barriers working together," said Lynn Bonham, PhD, Senior Director of Translational Pharmacology at Aptevo. Bonham continued, "Our new trispecific molecules, APVO452 and APVO451, are built to tackle tumors on several fronts at once. They lock onto the tumor itself, activate T cells to attack it, and reprogram suppressive immune cells so they help the fight instead of holding it back." Looking Ahead With the addition of APVO452 and APVO451, Aptevo now has eight bispecific and trispecific therapeutic candidates, including five molecules that employ the CRIS-7-derived CD3 pathway. This dual strategy positions the Company at the forefront of next-generation T cell engagers, with a pipeline purposefully designed to address both hematologic and solid tumor cancers such as AML, lung and breast cancers and multiple other solid tumor types. About Aptevo Therapeutics Aptevo Therapeutics Inc. (Nasdaq:APVO) is a clinical-stage biotechnology company focused on developing novel bispecific and trispecific immunotherapies for the treatment of cancer. The Company has two clinical candidates. Mipletamig is currently being evaluated in RAINIER, a two-part Phase 1b/2 trial for the treatment of frontline AML in combination with standard-of-care venetoclax + azacitidine. Mipletamig has received orphan drug designation ("orphan status") for AML according to the Orphan Drug Act. ALG.APV-527, a bispecific conditional 4-1BB agonist, only active upon simultaneous binding to 4-1BB and 5T4, is being co-developed with Alligator Bioscience and is being evaluated in a Phase 1 clinical trial for the treatment of multiple solid tumor types likely to express 5T4. The Company has six preclinical candidates with different mechanisms of action designed to target a range of solid tumors. All pipeline candidates were created from two proprietary platforms, ADAPTIRand ADAPTIR-FLEX. The Aptevo mission is to improve treatment outcomes and transform the lives of cancer patients. For more information, please visit www.aptevotherapeutics.com. Safe Harbor Statement This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical fact, including, without limitation, Aptevo's expectations about the activity, efficacy, safety, tolerability and durability of its therapeutic candidates and potential use of any such candidates, including in combination with other drugs, as therapeutics for treatment of disease, its expectations regarding the effectiveness of its ADAPTIR and ADAPTIR-FLEX platforms, whether pre-clinical studies of Aptevo's trispecific candidates APVO452 and APVO451 will show the desired anti-tumor efficacy, mechanism of action and safety profile and whether APVO452 and APVO451 will function with new mechanisms of action compared to our previous candidates and synergistically induce a biological response, whether APVO452 and APVO451 will demonstrate the ability to fight a range of solid malignancies, including prostate cancer, whether Aptevo's provisional patent applications will result in patents or adequately protect APVO452 and APVO451, statements related to the progress of Aptevo's clinical programs, including statements related to anticipated clinical and regulatory milestones, whether further study of mipletamig in a Phase 1b dose optimization trial focusing on multiple doses of mipletamig in combination with venetoclax + azacitidine on a targeted patient population will continue to show clinical benefit, whether Aptevo's final trial results will vary from its earlier assessment, the possibility and timing of interim data readouts for ALG.APV-527, development and continued development of Aptevo's current and potential future molecules, the anticipated timing of the initiation of preclinical studies of APVO452 and APVO451, APVO452's and APVO451's future development and efficacy with respect to addressing multiple solid tumor types, including prostate cancer, statements related to Aptevo's ability to generate stockholder value, whether Aptevo will continue to have momentum in its business in the future, and any other statements containing the words "may," "continue to," "believes," "knows," "expects," "optimism," "potential," "designed," "promising," "plans," "will" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based on Aptevo's current intentions, beliefs, and expectations regarding future events. Aptevo cannot guarantee that any forward-looking statement will be accurate. Investors should realize that if underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could differ materially from Aptevo's expectations. Investors are, therefore, cautioned not to place undue reliance on any forward-looking statement. There are several important factors that could cause Aptevo's actual results to differ materially from those indicated by such forward-looking statements, including a deterioration in Aptevo's business or prospects; further assessment of preliminary or interim data or different results from later clinical trials; adverse events and unanticipated problems, adverse developments in clinical development, including unexpected safety issues observed during a clinical trial; and changes in regulatory, social, macroeconomic and political conditions. For instance, actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the uncertainties inherent in the results of preliminary or interim data and preclinical studies being predictive of the results of later-stage clinical trials, initiation, enrollment and maintenance of patients, and the completion of clinical trials, the availability and timing of data from ongoing clinical trials, the trial design includes combination therapies that may make it difficult to accurately ascertain the benefits of mipletamig, expectations for the timing and steps required in the regulatory review process, expectations for regulatory approvals, the impact of competitive products, our ability to enter into agreements with strategic partners or raise funds on acceptable terms or at all and other matters that could affect the availability or commercial potential of Aptevo's product candidates, business or economic disruptions due to catastrophes or other events, including natural disasters or public health crises, geopolitical risks, including the current war between Russia and Ukraine and the wars between Israel and Hamas, Israel and Iran, and any other military event that could evolve out of any of the current conflicts and macroeconomic conditions such as economic uncertainty, imposition of tariffs, rising inflation and interest rates, continued market volatility and decreased consumer confidence. These risks are not exhaustive, Aptevo faces known and unknown risks. Additional risks and factors that may affect results are set forth in Aptevo's filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K for the fiscal year ended December 31, 2024, and its subsequent reports on Form 10-Q and current reports on Form 8-K. The foregoing sets forth many, but not all, of the factors that could cause actual results to differ from Aptevo's expectations in any forward-looking statement. Any forward-looking statement speaks only as of the date of this press release, and, except as required by law, Aptevo does not assume any obligation to update any forward-looking statement to reflect new information, events, or circumstances. CONTACT: Miriam Weber Miller Head, Investor Relations & Corporate Communications Aptevo Therapeutics Email: IR@apvo.com or Millerm@apvo.com Phone: 206-859-6628 SOURCE: Aptevo Therapeutics