Donanemab-AZBT

Alzheimer’s disease has afflicted Hannah Richardson’s family for generations. A rare genetic mutation, passed down from her great-grandmother, has struck her relatives with the first signs of memory loss at an average age of 39. Last year, her uncle died with dementia at 42. Her mother, now the same age, is in the moderate stages of the disease. Richardson, 24, has joined a clinical trial hoping to avoid the same fate. She will be one of the youngest people ever to receive an experimental drug intended to prevent dementia-linked amyloid plaques from building up in the first place. “I knew immediately I wanted to be a part of it,” she told Endpoints News in an interview. The study, helmed by Washington University School of Medicine in St. Louis, will enroll people who carry genes for inherited forms of Alzheimer’s, but who aren’t expected to develop their first symptoms for another 11 to 25 years. “Amyloid pathology can be identified one to two decades before people develop symptoms,” Eric McDade, a professor of neurology who is leading the study, told Endpoints. “What we’re trying to do is actually show that we can prevent that amyloid pathology from developing.” They’ll use an experimental Eli Lilly drug called remternetug. It is similar to the Indianapolis drugmaker’s drug Kisunla, which was approved last summer, but is administered as a quarterly injection instead of a monthly infusion. The trial is expected to last at least six years and cost more than $130 million. Most of the funding, an estimated $98.3 million, will come from the National Institutes of Health. If successful, it could provide one of the most dramatic tests yet of the much-debated amyloid hypothesis. “This is really going to be a landmark study,” Howard Fillit, chief science officer of the Alzheimer’s Drug Discovery Foundation, told Endpoints. “I believe it is the earliest treatment trial that has ever been conducted.” For years, drugmakers failed to make a dent in Alzheimer’s, either because they went after the wrong form of amyloid or tested the drugs in patients too deep in the throes of the disease. Two approved drugs, Eisai and Biogen’s Leqembi and Lilly’s Kisunla, are marketed for mild cognitive impairment, the earliest symptomatic stage of Alzheimer’s where brainpower noticeably begins to fade. But the effects are modest, and the companies have now started identifying patients with blood tests and brain scans, but no outward signs of memory loss, to start treatment earlier. Those tests are now underway. Results from Lilly’s trial could come as soon as 2027, and Eisai’s study is scheduled to start wrapping up in 2028. But the WashU Medicine study aims to treat people even earlier, before there’s almost any progression of the disease in the brain. It’s a bet that they might be able to prevent, not just slow, the disease. “Most of the people that will start this study won’t have any amyloid in their brain that we can detect,” McDade said. “We’re calling it primary prevention.” Fillit compared the approach to using statins in young people with high cholesterol before they develop coronary artery disease. “Except these are people that don’t even have the biomarker evidence,” he added. Last week, Richardson went in to get her blood and spinal fluid collected and her brain scanned. The tests will provide a baseline for doctors to track her progress in the years to come. “I’ve been aware of Alzheimer’s in my family since a young age, so I’ve had a long time to kind of sit with that,” Richardson said. “But now, being the one going through the tests and the imaging and receiving the first dose of the medication in a few weeks, it definitely is eye-opening.” The study is part of the Dominantly Inherited Alzheimer Network Trials Unit, or DIAN-TU, a closely-watched effort at WashU Medicine to investigate drugs in people with rare mutations who are almost guaranteed to develop the disease. Richardson’s mom and uncle participated in another DIAN-TU study when they were in their early 30s. Most people in the study already had amyloid plaques by the time they got an experimental Roche drug called gantenerumab. Although the drug seemed to lower amyloid, it didn’t slow cognitive decline. McDade, the trial leader, originally planned to use gantenerumab again in a primary prevention study, but after it failed in Roche’s own trials in 2022, he looked for another option. He landed on remternetug, which seemed like a simpler alternative to Leqembi, infused every two weeks, and Kisunla, infused every month. “If we really, truly have to treat people for a decade or more, you certainly don’t want them coming in for infusions every two weeks,” McDade said. Richardson and about 240 other participants in the study will get an injection of remternetug or a placebo every three months for two years. “What we can’t do, kind of ethically and realistically, is run a placebo-controlled trial for 20 years,” McDade said. As a comparison, the study will include family members who don’t carry the Alzheimer’s risk genes. Measuring amyloid on brain scans is the primary outcome. After the initial two years, people with the mutations can continue to get injections of the drug in an open-label extension for another four years. Beyond that, McDade expects that people will need less frequent dosing, but the details of how often that will be are to be determined. Richardson is clear-eyed about her family’s medical history. “I hope there is benefit,” she said. “But even if that is not the outcome, just collecting this data is still so important for helping people down the line not suffer the way that people are suffering now, and that’s really important to me.”

抗体药物（Antibody Therapeutics）作为生物制药领域的重要组成部分，在过去几十年中取得了显著进展，并在肿瘤、自身免疫性疾病、感染性疾病等领域展现了巨大的临床价值。未来10年，抗体药物的发展将受到技术进步、市场需求、政策环境等多重因素的影响，呈现出多元化、精准化、智能化的趋势。以下从多个角度详细分析未来10年抗体药物的发展趋势： 1. 技术突破驱动创新 双抗/多特异性抗体：针对复杂疾病（如肿瘤、自身免疫病）的双靶点或多靶点抗体将加速研发，解决单一靶点的耐药性问题（如罗氏的Hemlibra、强生的Amivantamab）。 抗体偶联药物（ADC）：通过优化抗体、连接子和毒素的组合（如Enhertu、Trodelvy），提高肿瘤杀伤特异性，并拓展到非癌适应症（如炎症性疾病）。 AI与计算设计：人工智能将加速抗体开发，通过预测表位、优化亲和力/稳定性（如DeepMind的AlphaFold、Absci等公司），缩短研发周期（传统需3-5年，未来可能缩短至1-2年）。 新型抗体形式：纳米抗体（如赛诺菲的Cablivi）、多结构域抗体（如双抗融合蛋白）将改善组织穿透性（尤其在实体瘤和中枢神经系统疾病中）。2. 适应症拓展：从肿瘤到慢病 肿瘤领域：继续主导市场，但重点转向联合疗法（如PD-1/L1抗体联合ADC或双抗）、罕见靶点（如Claudin 18.2、HER3）及实体瘤突破（目前抗体药多用于血液瘤）。 自身免疫疾病：靶向IL-17、IL-23、JAK等通路的抗体（如司库奇尤单抗、乌司奴单抗）将覆盖更多患者，并探索治愈性疗法（如B细胞耗竭疗法）。 神经退行性疾病：针对阿尔茨海默病（Aβ、Tau蛋白抗体）、帕金森病的抗体药物可能迎来突破（如礼来的Donanemab已获FDA加速批准）。 抗感染领域：广谱抗病毒抗体（如针对流感、HIV、新兴病毒）和抗耐药菌抗体（如针对MRSA）研发加速，应对公共卫生危机。3. 生产与商业化革新 连续化生产（Continuous Manufacturing）：替代传统批次生产，降低成本（单抗成本或降至$50/g以下），提升产能灵活性。 模块化工厂与AI质控：小型化、自动化生产设备（如赛默飞的Hyris系统）助力新兴药企快速响应市场需求。 生物类似药竞争加剧：随着阿达木单抗（修美乐）、贝伐珠单抗（安维汀）等重磅药物专利到期，生物类似药将压低价格（预计2030年生物类似药市场超300亿美元）。 患者可及性策略：通过“按疗效付费”（Value-based Payment）和新兴市场本地化生产（如中国、印度）扩大覆盖。4. 全球市场格局演变 中国崛起：本土企业（如信达、君实、荣昌生物）从Fast-follower转向First-in-class，依托政策支持（如“十四五”生物医药规划）和资本投入，ADC、双抗领域或诞生全球重磅产品。 国际化竞争与合作：跨国药企（如罗氏、默沙东）与Biotech的License-in/out交易更频繁，共同分担研发风险。 新兴技术公司受资本青睐：专注ADC、双抗平台、AI设计的公司（如Immunogen、Seagen、Generate Biomedicines）估值持续走高。5. 监管与政策趋势 加速审批通道普及：FDA的突破性疗法认定（BTD）、中国的附条件批准等政策将更广泛应用，尤其针对罕见病和未满足临床需求。 真实世界证据（RWE）：替代部分III期临床试验数据，支持抗体药适应症扩展（如PD-1药物的跨癌种应用）。 安全性要求升级：复杂抗体（如双抗、ADC）的免疫原性、脱靶毒性监管趋严，推动更精准的临床前模型（如类器官、数字孪生）。6. 挑战与风险 耐药性与疗效瓶颈：肿瘤微环境抑制抗体渗透、抗原逃逸突变（如EGFR C797S）需新策略应对。 生产成本与定价压力：尽管技术进步，高剂量抗体（如阿尔茨海默病药物需每月静脉注射）仍面临医保支付挑战。 临床需求与商业化的平衡：针对超罕见病（患者数<千人）的抗体药需创新商业模式（如“全球定价+患者援助计划”）。总结 未来10年，抗体药将向更精准、更智能、更可及的方向发展，核心驱动力包括： 技术融合（AI+生物技术+工程学）， 未满足临床需求（实体瘤、神经疾病等）， 全球化竞争与合作。中国等新兴市场或成为创新策源地之一，但需突破核心技术（如细胞株构建、大规模纯化）和国际化能力瓶颈。 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！ 请注明：姓名+研究方向！ 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。