Balstilimab

Endpoints News sat down with Jeff Bluestone and Stephen Dilly after Sonoma Biotherapeutics announced earlier this week that Bluestone was stepping down from his CEO role and Dilly would be taking his place. Bluestone, a prominent academic and the first head of the Parker Institute for Cancer Immunotherapy, founded Sonoma six years ago to develop regulatory T cell therapies. On Monday, he handed the reins to Sonoma over to Dilly, the former CEO of Codexis and Sierra Oncology . This conversation has been substantially edited for length and clarity. Lei Lei Wu: Jeff, I’ll start with you. Not too long ago, we met to speak about Sonoma’s first clinical data. How long has this transition been in the works for? And why now? Jeff Bluestone: We needed to go find a great CEO. It took me a little bit more than 24 hours to do that, so we started the search a little while ago. But, very excited to have Stephen come on board. I just felt it was the right time to turn the reins over, because I think the company is a really great place right now. Someone emailed me this morning and said it’s a little bit like [Los Angeles Dodgers Hall of Famer] Sandy Koufax . In his last year, he was an All-Star pitcher, shutouts every day. And I figured, might as well leave on a good note. Plus my grandkids, my wife and the rest of my life had a big impact as well. Wu: Are you a Dodgers fan? Bluestone: No, not at all. My father grew up a New York Giants fan, and we hated the Yankees and we hated the Dodgers. Wu: What’s next for you? Bluestone: It’s hard to use the word “retire.” It feels like a definitive ending, which it won’t be. I’m really lucky that Stephen is interested in having me continue to advise the company, which I will, and I’ll be on the board. Aside from that, I’m on the Gilead board, which I’ll continue to do, and then I want to spend some time thinking about how I can help young people. The idea of being able to help young student scientists is exciting to me. I’ll probably go back to UCSF for journal clubs and lab meetings and the like. And then finally, just do some of the things in life that I sacrificed over these many years. Wu: Stephen, turning to you now. What made you interested in this role? Stephen Dilly: One of the things that I believe in very strongly is that people are ideally suited to stages of journeys. What Jeff has done over the last six years at Sonoma, something that I would not be able to do, is take basic science and incredible insights and turn that from a concept into something that’s ready for going into people. I’m a drug developer. Dyed-in-the-wool drug developer. It’s a different thought process. The research process is inclusive and exploratory. The development process is very targeted. A lot of it is about the way you look at challenges, the way you address them, the way you move forward. And this company is absolutely in my sweet spot. A lot of the raw material is here to do something quite remarkable. — Lei Lei Wu → T cell receptor specialist Adaptimmune announced on Monday that its CEO of six years, Adrian Rawcliffe , left “in connection with the company’s restructuring.” It’s the end of an era for Adaptimmune, which won approval last year for the first cell therapy based on T cell receptors. Known as Tecelra , the therapy was approved for a rare cancer called synovial sarcoma. The news comes after Adaptimmune sold Tecelra , among other assets, and laid off nearly two-thirds of its workforce. Most of the company’s executives departed with the layoffs, and Rawcliffe is the latest to do so. Chris Hill is now CEO as well as CFO. And the company’s longtime COO William Bertrand also left “in connection with the restructuring,” Adaptimmune said Monday . → Former FDA Commissioner Scott Gottlieb has joined UnitedHealth Group ’s board, the massive health insurer said Tuesday. Gottlieb also sits on the boards of Pfizer and Illumina . The move comes as UnitedHealth has faced increasing pressure on its business with higher medical costs and scrutiny over insurance denials , as well as a ransomware attack on its Change Healthcare business. Former CEO Andrew Witty stepped down in May and was replaced by longtime UnitedHealth chief Stephen Hemsley . Its stock is down 38% this year. “We welcome his deep expertise and thought leadership as we strive to help people live healthier lives and make the health system work better for everyone,” Hemsley said in a news release . → Juby Chandy will have new responsibilities at GSK on Dec. 1: The current GSK India CFO has been named VP of finance for the Asia Pacific region. Scrolling is required to go through Chandy’s 17-year career at GSK, where he has also served as area finance director for Southeast Asia and head of finance, general medicines, global pharma, among other roles. In October, Emma Walmsley conducted her last quarterly report at GSK before commercial chief Luke Miels takes over as CEO. → Philina Lee will be the next CEO at Sydney-based cancer biotech AdvanCell on Jan. 1. She’ll replace Andrew Adamovich , who will have a new role as managing director, Australia. Lee will take over a company that just stocked up on cash with a $112 million Series C in February. She had an 11-year run at Blueprint Medicines and was chief commercial officer until Sanofi bought the Ayvakit maker for more than $9 billion this year. (Incidentally, her former boss Kate Haviland said on LinkedIn this week that she’ll “continue contributing to the life sciences ecosystem” as a senior advisor at Jefferies .) AdvanCell’s lead program 212Pb-ADVC001 is a PSMA-targeting radioligand for patients with prostate cancer. “Philina’s leadership further strengthens our ability to establish the United States as a global hub while continuing to deliver innovation from Australia and cementing our position as a leader in targeted alpha radiotherapies,” Adamovich said in a statement . → At another Australian drugmaker, Mesoblast has tapped Bristol Myers Squibb and Allergan vet James O’Brien as CFO. O’Brien will be based in the US and was CFO at Cognition Therapeutics (2019-23) and Faron Pharmaceuticals (2023-24). Mesoblast’s head of finance Andrew Chaponnel had been interim finance chief since Josh Muntner hit the exit in 2021. At long last, the FDA approved Mesoblast’s mesenchymal stromal cell therapy Ryoncil in December 2024. → Gilead general counsel Deborah Telman will leave on Dec. 5, according to a terse SEC filing . Telman replaced Brett Pletcher as EVP, corporate affairs and general counsel in August 2022. Gilead did not provide any details about Telman’s departure. → As part of a restructuring, Nxera Pharma is trimming its leadership team, going from 10 execs to seven by March 2026 in a bid to cut operating expenses. Nxera is also pruning its workforce by about 15% across Japan and the UK, and focusing its sights on obesity, metabolic and endocrine therapies. While the company is cutting jobs elsewhere, it has recruited Patrik Foerch as CSO and president of Nxera Pharma UK , taking over the reins from Matthew Barnes . Foerch was CSO of Peptone , ran preclinical drug discovery at Sitryx , and had a 13-year stint at UCB . Nxera hopes that the cost-cutting measures will help the company reach its net sales forecast of 50 billion yen in 2030. → With ex- NGM Bio CEO David Woodhouse now at the controls, immunomodulatory upstart Nuvig Therapeutics has welcomed Celia Lin as CMO. Lin joined Santa Ana Bio in the same capacity shortly after the Versant biotech’s $125 million Series B last summer, but she stepped down nine months later. Peer Review covered Lin’s appointment as CMO of Vera Therapeutics and her departure in early 2024, when she was replaced by Robert Brenner . Nuvig disclosed a nine-figure Series B of its own last year and is evaluating NVG-2089 in chronic inflammatory demyelinating polyneuropathy (CIDP) and immune thrombocytopenia. → Paolo Tombesi is retiring after CFO posts at multiple drugmakers over the past 25 years. He’s handing the job at Athena Countouriotis ’ Avenzo Therapeutics to Scott Lipman , who was promoted to CBO last year and will retain both duties. Tombesi helped Countouriotis steer their prior biotech, Turning Point Therapeutics , toward a multibillion-dollar exit to Bristol Myers Squibb . Along with Lipman, they reunited for Avenzo, raising more than $440 million over the past few years for small molecules and antibody-drug conjugates licensed from Chinese partners. Prior to that, Tombesi built his CFO chops at Epizyme and Insmed after holding regional CFO posts at Novartis and Bristol Myers. → 4D Molecular Therapeutics has found a new CFO after Uneek Mehra ’s departure in July. Kristian Humer held this job title at Foghorn Therapeutics and Viridian Therapeutics after 11 years with the healthcare investment banking group at Citi . Mehra took the CFO job at BridgeBio Oncology Therapeutics , or BBOT. Shares $FDMT surged this summer when 4DMT notched a Phase 2 win with its gene therapy 4D-150 for diabetic macular edema, and there’s been an upward trend ever since. → Andy Nichols announced on LinkedIn that he’s “finally pulling the plug and disconnecting from corporate life, at least for a while,” after 40 years in the industry and two years at Jazz Pharmaceuticals as SVP of research, nonclinical development and clinical pharmacology. By the way, Zymeworks has named EcoR1 Capital partner Scott Platshon as acting chief investment officer. Jazz and Zymeworks outlined a Phase 3 win this week with their HER2 bispecific Ziihera in gastroesophageal adenocarcinoma, and their stock prices popped as a result. → Abraxane developer José Iglesias ’ first day as chief medical affairs officer at Agenus was Nov. 10, according to a Tuesday press release . Iglesias had a brief turn as CMO at Tim Lu ’s Senti Bio in 2020, and he reemerged as consulting medical chief for Panavance Therapeutics . Agenus is combining its anti-CTLA-4 antibody botensilimab with its PD-1 candidate balstilimab . Known colloquially as BOT/BAL , the combo is in Phase 3 for microsatellite-stable colorectal cancer. → French ADC maker Adcytherix has hired a pair of execs after a host of investors participated in its €105 million Series A . Medical chief Jan Schellens just held the same position at another ADC developer in France called Skymab Biotherapeutics , and he was CMO of Dutch biotech Byondis from 2019-23. Finance chief Jaime Arango had multiple roles over a nine-period at Merck , and he’s been CFO at Medincell and TreeFrog Therapeutics . → Eduardo Dunayevich will help steer the clinical direction of San Francisco-based Neurona Therapeutics , the CNS cell therapy startup that nabbed $ 102 million earlier this year for its epilepsy program. The new CMO was VP of clinical development and leader of the VMAT2 franchise at Neurocrine Biosciences . Dunayevich has been in industry for a quarter-century, making stops at Eli Lilly , Orexigen Therapeutics , Amgen , Takeda , Annexon Biosciences and Greenwich Biosciences along the way. → Elicio Therapeutics , co-founded by former MIT professor Darrell Irvine , has selected Marc Wolfgang as chief technology officer. Wolfgang just finished a stint as SVP of technical development and operations over at Flagship ’s Sail Biomedicines , which cut 30% of its staff in July. Wolfgang’s résumé also includes gigs at BioNTech , Cerulean Pharma , Momenta Pharmaceuticals , Millennium Pharmaceuticals , Biogen and Boehringer Ingelheim . → Kameel Farag helped set up cell therapy maker Aspen Neuroscience for a potential IPO (with a $115 million Series C disclosed Thursday). Now, a few months after leaving the CFO post at Aspen, he’s returning to the role on an interim basis at Akari Therapeutics . Farag built up his finance acumen during a 16-year career at Amgen and a three-year stint at Ionis . Akari has two ADC programs in preclinical development. → After bagging Y-mAbs in a $412 million all-cash deal , specialty drugmaker SERB Pharmaceuticals is bringing its CMO into the fold. Vignesh Rajah will serve in the same role of medical chief at SERB. Besides Y-mAbs, Rajah had roles at Sanofi and Wyeth , as well as a decade-long career at GSK. SERB picked up Y-mAbs and its neuroblastoma treatment Danyelza in August, hoping to further expand upon its own portfolio of more than 70 drugs. → Mosaic Therapeutics CEO Thomas Fuchs is already making an impact in his first month on the job, bringing in Samsara BioCapital venture partner Stephen Shuttleworth as CSO. AstraZeneca vet Barry Davies is retiring from the position and will be “on extended gardening and travel leave,” according to his LinkedIn. Shuttleworth was CSO, COO and executive director at Karus Therapeutics , and he chaired the scientific advisory board at the end of his 12-year career with the company. → To the Dallas metro area we go, where OncoNano Medicine has lassoed Brent Sorrells as COO. Sorrells spent eight years with Allakos , where he was promoted to VP of product development and strategy in mid-2024. Concentra Biosciences scooped up the biotech earlier this year, setting off a chain reaction of similar acquisitions for Kevin Tang . OncoNano is developing a STING agonist called ONM-501 for solid tumors. → Edgewise Therapeutics has welcomed Chris Martin to the board of directors, following the appointment of CFO Michael Nofi . Martin helped launch the COPD treatment Ohtuvayre as chief commercial officer at Verona Pharma . Merck bought Verona this summer for $10 billion. Lydia Ramsey Pflanzer contributed to this edition.

转自©氨基观察-创新药组原创出品作者|沙晓威免疫治疗进入“后PD-1时代”，迭代与突破正成为主旋律。当众多创新靶点尚在验证途中，BioNTech正选择将目光重新投向CTLA-4这一老靶点身上。作为全球首个问世的免疫检查点抑制剂，CTLA-4抑制剂高开低走后沉寂许久。在最新研发日中，BioNTech则将新一代CTLA-4单抗Gotistobart纳入优先免疫调节管线，沉寂多年的CTLA-4再度回归行业视野。凭借分子设计的双重创新，Gotistobart在早期临床中展现出增效减毒的潜力，提高了安全性窗口与持续疗效，为PD-1耐药患者带来突破性希望。眼下，BioNTech把CTLA-4重新推到幕前，意在抢夺下一代IO的基石。创新总是有着矛盾而迷人的两面性，不到最后一刻，永远不能对一款药物下结论。那么，老靶点的新生，会成为下一代免疫治疗的破局关键吗？/01/老靶点的新生在免疫治疗的发展历程中，CTLA-4的发现早于PD-1，却走出了截然不同的发展轨迹。作为首个打开免疫治疗大门的靶点，CTLA-4单抗以全身免疫激活的机制开辟了全新治疗路径，但也因固有缺陷长期处于PD-1的光环之下。与PD-1单抗20余款产品上市盛况不同，截至目前，全球获批的CTLA-4单抗仅有两款，分别是百时美施贵宝的Ipilimumab（Y药）和阿斯利康的Tremelimumab。市场表现也与PD-1抑制剂相差悬殊：2024年，K药的全球销售额近300亿美元，而Y药的同期销售额仅为25.3亿美元，不足K药的十分之一，甚至一大部分的占比是基于与PD-1单抗Nivolumab联用的适应症。安全性问题是制约CTLA-4抗体发展的核心瓶颈之一。早期CTLA-4抗体的作用机制直接：通过无差别抑制削弱Tregs的免疫抑制作用，进而激活全身免疫反应。缺点就是无法区分肿瘤与正常组织中的Tregs，易引发严重的免疫相关不良反应（IrAEs）。疗效上的劣势则让CTLA-4彻底被PD-1掩盖。2014年，K药、O药相继上市，CTLA-4抗体在黑色素瘤、非小细胞肺癌（NSCLC）等核心适应症中表现逊色。以黑色素瘤为例，Y药治疗的客观缓解率（ORR）仅10%-15%，而K药的ORR可达30%-40%，部分亚型甚至能突破50%。即便是联合治疗场景，CTLA-4抗体也多处于“辅助地位”。比如Tremelimumab目前获批的适应症均为与O药联合治疗。尽管发展受限，CTLA-4的研究从未停滞，而是朝着精准化方向转型。BioNTech从OncoC4引进的新一代CTLA-4单抗Gotistobart正是这一转型思路的典型代表，其分子设计通过双重创新实现了对传统CTLA-4抗体的突破。一方面，借助pH敏感型抗体技术，Gotistobart与CTLA-4结合形成的复合物被细胞内吞后，会在溶酶体的酸性环境中发生解离，使CTLA-4蛋白能够重返细胞表面重新发挥作用，避免了传统抗体导致的CTLA-4内吞降解，大幅提升了药物的治疗窗口。另一方面，通过Fc段的工程化改造，Gotistobart能够更高效地招募免疫效应细胞，精准清除TME中的Tregs，同时减少对正常组织的影响。正如OncoC4所言，这种机制使Gotistobart具备了长期、重复给药的潜力，为持续控制肿瘤提供了可能。早期临床数据初步验证了其潜力：在针对ICI耐受的NSCLC患者开展的1/2期临床试验中，Gotistobart单药治疗的ORR达29.6%，DCR高达70.4%，这一结果对PD-1耐药人群具有突破性意义。基于此，今年10月，该药物获得NMPA授予的突破性疗法认定，用于治疗PD-1耐药的晚期NSCLC患者，成为首个在该适应症中获得突破性认定的新一代CTLA-4抗体。/02/BioNTech的IO双支柱将Gotistobart纳入优先免疫调节管线，是BioNTech构建下一代IO治疗体系的关键布局。在其优先免疫调节剂研发管线中，PD-L1/VEGF双抗Pumitamig与CTLA-4单抗Gotistobart构成两大核心支柱，分别代表了多靶点协同增效与老靶点升级改造的发展策略。作为BioNTech重点布局的下一代IO基石，Pumitamig的核心优势在于同时结合PD-L1与VEGF两个靶点，一方面阻断PD-1/PD-L1信号通路，激活效应T细胞的抗肿瘤功能，另一方面抑制VEGF介导的肿瘤血管生成，改善肿瘤微环境。目前，BioNTech已推动Pumitamig20项临床落地，除了小细胞癌、NSCLC和三阴性乳腺癌的三期临床，更是加速推进泛癌种布局以及与化疗、ADC、新型免疫靶点药物（如PVRIG抑制剂BNT3213）等不同且新颖的联合疗法研究。相比之下，尽管是首次进入BioNTech的重点研发项目名单，但从即将推进的研究布局来看，Gotistobart的定位绝非对现有IO药物的简单补位，而是要成为BioNTech下一代IO治疗的核心基石之一。BioNTech在研发日中明确提出，Gotistobart的研发目标是“探索新的组合以确定潜在的未来治疗标准”。Gotistobart的“魅力”在于循环利用的机制以及针对PD-1耐药人群的潜力，这为其开展多样化的联合治疗研究提供了基础。从研发日的报告上看，BioNTech计划围绕Gotistobart启动了覆盖多个癌种、多种联合模式的研究：开展单药治疗针对二线及以上鳞癌NSCLC患者的3期临床试验，明确单药治疗潜力；开展联合K药治疗宫颈癌的2期研究，以明确CTLA-4、PD-1的协同效应潜力；还有联合核药PLUVICTO治疗转移性去势抵抗性前列腺癌的早期研究；以及开展覆盖多种实体瘤的早期临床研究，进一步挖掘潜在肿瘤适应症。其中，与PLUVICTO联合治疗前列腺癌的研究极具看点。2025年ASCO大会公布的1期研究初步结果显示，该联合方案耐受性良好，且临床前模型已证实，放射治疗能够选择性扩增并激活肿瘤微环境中的Tregs，这恰好与Gotistobart的作用机制匹配此外，Gotistobart与mRNA疫苗BNT116的联合研究也已启动，借助mRNA疫苗引导T细胞向肿瘤抗原特异性分化的能力，结合Gotistobart清除免疫抑制细胞的作用，有望实现更持久的抗肿瘤免疫记忆。尽管Gotistobart目前还处于早期适应症扩张和验证阶段，但是BioNTech的双支柱策略已经清晰：Pumitamig通过多靶点协同作用提升免疫治疗疗效，覆盖广泛实体瘤治疗需求；Gotistobart目前则聚焦PD-1耐药以及肿瘤晚期等难治人群，两者构成了肿瘤全周期的免疫治疗。/03/CTLA-4值得期待Gotistobart的进展与BioNTech的战略布局只是CTLA-4赛道升温的一个缩影，全球药企正从分子设计优化、双抗研发、联合治疗等多个维度挖掘这一靶点的潜力。在单抗领域，Agenus公司的Botensilimab采用人源化Fc段增强设计，通过强化ADCC效应提升对肿瘤微环境中Tregs的清除效率，与ipilimumab相比，能同时激活先天与适应性免疫系统，尤甚至在冷肿瘤中表现潜力。其在与Balstilimab（PD-1抑制剂）联合治疗微卫星稳定型转移性结直肠癌患者的2期临床中，实现了42%的两年生存率，平均OS为20.9个月，而对于已经接受过4线或更多治疗的患者，BOT/BAL的联合治疗方案可以实现两年生存率43%，ORR为19%。国产药企在CTLA-4靶点的设计同样表现亮眼，比如和铂医药的HBM4003。作为一款全人源重链抗CTLA-4抗体，HBM4003仅有76kDa，小分子的优势，能够更高效穿透肿瘤组织，提升肿瘤微环境中的药物浓度，同时，其Fc段经过突变改造，显著增强ADCC活性，可精准清除高表达CTLA-4的肿瘤浸润Tregs。不久前公布的2期临床数据显示，在既往接受过多种治疗的MSS转移性结直肠癌患者中，每21天接受HBM4003联合替雷利珠单抗治疗的ORR达34.8%，DCR60.9%，mPFS为4.2个月，且87.5%的相关不良事件为1、2级，安全性表现优异。双抗成为CTLA-4靶点的另一重要研发方向。康方生物的AK104是一款CTLA-4/PD-1双抗，同时阻断两个免疫检查点，实现协同激活免疫的效应。尽管热度低于PD-1/VEGF双抗依沃西，但公司计划通过联合策略挖掘其价值，近期宣布AK104与依沃西联用治疗胰腺癌术后辅助治疗的1期临床已完成首例给药。阿斯利康的Volrustomig同样是针对PD-1/CTLA-4的双抗，目前正在在NSCLC领域的研究正开展头对头K药的3期临床eVOLVE-Lung02，进度与实力不容小觑。联合治疗则持续拓展着CTLA-4的应用边界。BMS的“Y药+O药”组合已在黑色素瘤、NSCLC、肾癌等多个癌种中获得FDA批准，涉及十余项适应症；Tremelimumab与O药的联合方案已获批用于NSCLC治疗，与O药+铂类化疗的三联方案则拓展至前列腺癌一线。信达生物的IBI310则是国内研发进度领先的CTLA-4抗体，其与PD-1抑制剂信迪利单抗的联合方案在今年2月被CDE纳入优先审批，适应症为可切除的微卫星高度不稳定型或错配修复缺陷型结直肠癌患者的新辅助治疗。此外，CTLA-4抗体与ADC、核药、小核酸等新型疗法的联合也是研究方向，BioNTech探索的Gotistobart与核药PLUVICTO的联合，不仅是适应症的拓展也是机制的补充，为靶点价值的挖掘开辟了更多可能。总之，CTLA-4凭借独特的免疫调节机制与持续迭代的药物研发，有望摆脱PD-1的阴影，与多靶点药物、新型疗法形成协同，构建下一代IO治疗的基石。尤其是当PD-1的耐药及不敏感问题成为免疫治疗的核心挑战之际，CTLA-4则提供了另一条免疫调节途径。尽管过程仍充满挫折和不确定性，但是创新药的发展，从来都是螺旋上升的。随着新技术、新机制的出现，以及更多临床数据的涌现，那些曾经被否定的药物，也有可能重新焕发新的光芒。老靶点的新生，值得期待。#创新药时代来临##创新药##锂电池板块回落，赣锋锂业大跌#$云顶新耀(01952)$$康方生物(09926)$$荣昌生物(09995)$