ROR1

NM32 is a first-in-class half-life-enhanced T-cell engager targeting ROR1, a tumor associated antigen with broad expression in solid tumors and hematological malignancies Low molecular weight of NM32 allows to efficiently achieve higher tumor concentrations than larger immunoglobulin G molecules, the current standard format for CD3 engagers HORGEN, Switzerland, Oct. 30, 2024 (GLOBE NEWSWIRE) -- Numab Therapeutics AG (“Numab”) announced today the start of a Phase 1 clinical trial evaluating NM32, a next generation tri-specific immuno-oncology therapeutic targeting the receptor tyrosine kinase-like orphan receptor 1 (ROR1) and the T-cell receptor associated antigen CD3. The third binding moiety of NM32 targets serum albumin to provide half-life extension allowing for convenient bi-weekly dosing and to keep the lower molecular weight than immunoglobulin enabling efficient tumor penetration. “Generated from our proprietary Lambda-capTM and MATCHTM technology platform, NM32 represents a T-cell engager designed to help the patient’s immune system recognize and attack tumor cells. ROR1 is overexpressed on a wide spectrum of highly prevalent solid tumor indications but has very limited expression on normal tissue, making it an optimal antigen for a CD3 engager,” said David Urech, Ph.D., Founder and Chief Executive Officer of Numab Therapeutics. “We are pleased to start NM32’s clinical development path enabling us to potentially bring this novel therapy to patients with advanced solid tumors who are in need of treatment options that provide durable anti-tumor activity with a tolerable safety profile. Enrollment is progressing nicely, with patients completing the first treatment cycle of the initial dose level”, commented Martin Stern, Senior Vice President Clinical Science at Numab Therapeutics. “Despite the introduction of checkpoint inhibitors and several commercially available CD3 engagers for the treatment of hematological malignancies, there has been limited success in solid tumors mainly due to the lack of highly tumor-specific antigens allowing selective T-cell activation against tumor cells.” This multi-center Phase 1 study of NM32 is a dose-escalation trial to characterize the pharmacokinetic properties, pharmacodynamic effects and safety profile of NM32 and to select an optimal dosing regimen for further clinical development. It is planned to enroll up to 60 patients with solid tumors overexpressing ROR1 from major clinical sites across the United States. Generated preclinical data in non-human primates indicate a high potency and an excellent safety profile. About NM32 (NM32-2668)NM32 is a next generation tri-specific immuno-oncology drug targeting the receptor tyrosine kinase-like orphan receptor 1 (ROR1) and the T-cell receptor associated antigen CD3. The third domain targets serum albumin to provide half-life extension to allow convenient bi-weekly dosing. T-cell redirection using CD3 engagers is an established treatment modality showing high response rates and durable activity in hematological malignancies and has more recently also shown promising results for selected targets overexpressed in solid tumors. ROR1 is a clinically validated tumor associated antigen with overexpression in several indications with high unmet need including lung, breast, ovarian, endometrial, renal and gastric cancer and limited expression on healthy tissue. About Numab Therapeutics AGNumab Therapeutics AG is developing multi-specific antibody-based immunotherapies for inflammation and cancer. Reproducible plug-and-play therapeutic design process using proprietary platforms λ-CapTM and MATCHTM puts Numab in a unique position to overcome historical drug discovery barriers and build a pipeline of new and important medicines aimed to maximize patient benefits. Numab’s diverse research pipeline spans multiple therapeutic areas and creates the opportunity for the next generation of first-in-class and best-in-class medicines. Our lead candidate NM26, a unique multi-specific targeting IL-4/13 and IL-31 for best-in-class efficacy, is developed with a vision of delivering a lifelong cure to patients suffering from atopic dermatitis and other potential indications. Multiple partnerships with leading pharma companies validate the platform and development capabilities. For further information, visit https://www.numab.com. For further details, please contact: Numab TherapeuticsDavid UrechChief Executive Officerd.urech@numab.com Investor Contact: Patrick Till Meru Advisorsptill@meruadvisors.com

BOTHELL, WA, USA I October 29, 2024 I Immunome, Inc. (Nasdaq: IMNM), a biotechnology company focused on developing first-in-class and best-in-class targeted cancer therapies, recently presented promising preclinical data for IM-1021 and the associated proprietary ADC payload HC74. The results were presented in a poster entitled “Preclinical evaluation of IM-1021, a ROR1-targeted antibody-drug conjugate with a novel topoisomerase I linker payload” at the 36 th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona on October 24, 2024. The poster included preclinical results for IM-1021 in both liquid and solid tumors while also highlighting the enhanced ADME properties of HC74: Immunome expects to submit an IND for the IM-1021 program to the FDA in the first quarter of 2025. “We believe that transformative ADCs require matching the target with the right combination of antibody, linker, and payload. Based on this data, we continue to believe that IM-1021 is a promising preclinical candidate,” said Immunome’s Chief Scientific Officer Jack Higgins, Ph.D. “HC74’s differentiated profile, including substantial potency in chemo-resistant cell lines, provides intriguing opportunities for clinical development. We look forward to submitting the IM-1021 IND and starting clinical trials upon IND clearance to further validate these findings.” A copy of the poster is available in the “Events & Presentations” portion of Immunome’s website. About Immunome, Inc. Immunome is a clinical-stage targeted oncology company committed to developing first- and best-in-class targeted therapies designed to improve outcomes for cancer patients. We are advancing an innovative portfolio of therapeutics, drawing on leadership that previously played key roles in the design, development, and commercialization of cutting-edge targeted cancer therapies, including antibody-drug conjugate therapies (ADCs.) In addition to a portfolio of discovery-stage ADCs, our pipeline includes AL102, a gamma secretase inhibitor which is currently in a Phase 3 trial for treatment of desmoid tumors, as well as IM-1021, a ROR1 ADC, and IM-3050, a FAP-targeted radioligand, both of which are the subject of INDs expected to be submitted in the first quarter of 2025. For more information, visit www.immunome.com . SOURCE: Immunome

ROR1 CAR-T细胞疗法LYL797，在报告了临床死亡事件后，研发公司Lyell Immunopharma努力挣扎了4个月后，最终还是宣布停止对其的开发。 又一领先的ROR1 CAR-T管线停止，预示着ROR1靶点的不详。 患者死亡事件 2024年6月，Lyell报告了LYL797在三阴乳腺癌（TNBC）的I期临床中发生了一例死亡事件。 延伸阅读：实体瘤CAR-T患者死亡，股价跌去36% LYL797是一款基于Lyell公司专有的Gen-R技术平台开发的ROR1靶向CAR-T细胞，经过体外重编程使T细胞过表达蛋白质c-JUN，从而实现延缓衰竭并保持抗肿瘤功能。 在一项针对三阴乳腺癌的I期临床中，一名患者在第41天出现5级呼吸衰竭后死亡。此外，22%的患者中出现肺炎相关的剂量限制毒性，最常见的严重程度为3级或更高。 出现死亡事件的可能原因是ROR1靶点。 虽然ROR1在正常的肺部细胞中几乎不表达，但是在一些肺癌中呈现出异常高表达，而考虑到乳腺癌的特殊位置，一些患者实际上已经出现了乳腺癌的肺转移情况，这也使得一些患者出现肺部受累的情况。 LYL797挣扎无效 实际上，LYL797的这例死亡事件并没有引起美国FDA的警惕，临床并未暂停。Lyell公司仅是对临床进行了调整。 Lyell公司在2024年8月发布的第二季度财报中，还报告了LYL797的临床开发计划，包括针对三阴性乳腺癌（TNBC）或非小细胞肺癌（NSCLC）的临床继续进行，扩大标签至卵巢癌和子宫内膜癌，以及下半年提交针对多发性骨髓瘤和慢性淋巴细胞白血病的第二个IND。 很明显，死亡事件一开始并未打击到Lyell公司对于LYL797的信心。同时，该公司以TNBC研究的最高剂量队列中，40%的客观缓解率和60%的临床获益率，作为宣传的主要数据。 然后，期间不知道发生了什么，在距第二季度财报发布2个月多后，Lyell公司突然宣布要停止对LYL797的开发工作。 Lyell公司的首席执行官Lynn Seely在电话会议上，表明LYL797遇到了安全问题，并且没有“足够广泛的治疗窗口”。 另外，同时被放弃的还包括LYL845在内的TIL项目，停止LYL845的原因很明确，因为临床数据不符合持续开发的预期标准，导致其他TIL项目也一同被放弃了。 仍然死磕ROR1 小编猜测，LYL797的安全问题主要还是归因于，ROR1靶点比较难把控。 无独有偶，另一家ROR1开发公司Oncternal也报告了ROR1 CAR-T（ONCT-808）临床发生了死亡案例，同时预期ONCT-808治疗会发生不良事件。ONCT-808的临床已经停止，同时该公司现在正在考虑战略代替方案....... 延伸阅读： 2个核心管线同时暴雷，首席医疗官出走 ROR1 CAR-T：临床数据出炉 但是，ROR1开发难度高也不好使。在LYL797失败后，Lyell公司仍然在死磕ROR1 CAR-T。 因为Lyell公司在管线重组以后，新的核心管线赫然是以LYL797为基础开发的下一代的ROR1 CAR-T疗法LYL119。Lyell公司表示，LYL119能够在更低剂量下产生更好的疗效，并具有更广泛的治疗窗口。 ROR1 CAR-T的下一代产品LYL119在c-JUN过表达的基础上还增添了多项技术，例如敲除NR4A3基因进一步减少T细胞凋亡和衰竭，采用Stim-R™技术来强化信号转导，采用该公司的Epi-R™技术生产具有持久干细胞特性的T细胞。 最后在本身的技术之外，还结合了来自哈佛大学Wyss研究所的T细胞增强支架技术来强化临床获益，这种技术提供了一种能够模拟人体淋巴系统的支架材料，这种支架材料可以携带激活CAR-T需要的IL-2以及CAR-T上的CD3受体和CD28受体。 目前，该公司已经完成了LYL119的IND提交，预计将于今年或明年初启动针对铂类耐药卵巢癌或复发/难治性子宫内膜癌的1期临床。 CD19/CD20 CAR-T也挺香 另一个好消息是，Lyell公司也没有头铁到眼里只有ROR1。 在自身管线或是因为安全性、或是因为疗效被放弃，只剩下一根独苗LYL119后，Lyell公司将目光放到了外部，瞄准了一家小型CAR-T研发公司ImmPACT Bio，并以3000万美元现金和3750万股Lyell普通股对ImmPACT Bio进行收购。 被Lyell公司看中的是ImmPACT管线内一款CD19/CD20 CAR-T细胞候选产品IMPT-314。ImmPACT的其他管线（包括Claudin 18.2 CAR-T）优先级并不高。 IMPT-314是一款自体的、CD19/CD20双特异性CAR-T细胞，被开发用于治疗B细胞淋巴瘤和自身免疫性疾病。Lyell公司将优先开发IMPT-314的B细胞淋巴瘤适应症。 IMPT-314目前正在进行临床研究，预计将于今年晚些时候发布IMPT-314针对大B细胞淋巴瘤的临床数据。IMPT-314的关键试验预计将于2025年启动。 根据Lyell公司第二季度财报，截止2024年6月30日，拥有现金、现金等价物和有价证券4.911亿美元。 尽管收购ImmPACT需要花费一定现金，但是Lyell公司删减了管线的开发工作，仅剩2条临床管线，这使得Lyell公司的现金流支持公司运营至2027年。 小结 虽然但是，Lyell公司一口气停了好几个内部管线的开发，包括LYL797和全部的TIL项目，还是令人对其的研发实力产生质疑。 这一点也反应到了股市上，Lyell公司的股票持续下跌，截止本文发布前，已经跌至1美元以下，报9.27美分/股。 参考资料： 1.https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-acquire-immpact-bio-and-prioritizes-its 2.https://ir.lyell.com/news-releases/news-release-details/lyell-immunopharma-reports-business-highlights-and-financial-5 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·