Abstract 2904: CAT-179, an allogeneic NK cell product expressing HER2-CAR, IL-15 and TGFβ dominant negative receptor, durably regresses HER2-expressing xenograft tumors in mice

作者: Choi, Eugene ; Walsh, Meghan ; Pradhan, Kisha ; Alvarez, Andres ; Hamza, Bashar ; Nunez, Angela ; Gold, Joseph ; Moreno, Henry ; Picarella, Dominic ; Moore, Finola ; Daniel, Krista ; Malakian, Karl ; Johnson, Jennifer ; Suri, Vipin ; Wong, Keith H. ; Barandiaran, Alexia ; Marques, Marilyn ; Franco, Charlotte

AbstractWhile chimeric antigen receptor (CAR)-engineered immune cell therapies have been at the forefront of cancer immunotherapy for hematological malignancies, patients with solid tumors have yet to benefit from such therapies. Engineered, off-the-shelf, allogeneic natural killer (NK) cells are particularly attractive as cell therapies for solid tumors given their clinical safety, efficacy, and multimodal recognition of tumor cells.We describe here the pre-clinical pharmacokinetics, efficacy, biodistribution and safety of CAT-179, a novel allogeneic, cryopreserved CAR-NK cell therapy, in naïve animals as well as multiple xenograft models of HER2-amplified ovarian and gastric cancer. CAT-179 cells are engineered to express an optimized HER2-directed CAR to effectively target tumor cells, a transforming growth factor b (TGFβ) dominant negative receptor (DNR) to protect against TGFβ-mediated immunosuppression, and interleukin-15 (IL-15) to enhance NK cell persistence.A single intravenous (IV) dose of CAT-179 resulted in IL-15-dependent (p<0.0001) expansion and persistence of CAT-179 cells for at least 140 days in NOD-scid IL2Rgnull (NSG) mice, peaking at approximately 15,000 cells/µL of blood (by day 60). Persisting CAT-179 NK cell levels at day 60 were functionally active and significantly reduced tumor burden when challenged intraperitoneally (IP) with HER2+ SKOV3-luc tumor cells. No significant changes in body weight or condition were observed during this study.The therapeutic anti-tumor activity of CAT-179 against established tumors was assayed using two different xenograft models. In the first model, NSG mice were given an IP dose of 1 million SKOV3-luc tumor cells (derived from ovarian cancer) followed by either 4 million CAT-179 or control NK cells on days 4, 11 and 18. CAT-179 dosed animals showed a rapid and sustained 95% decline in tumor burden (p<0.0001) and a significant extension in survival relative to animals dosed with control NK cells (p<0.0001). In the second model, 1 million HER2+ N87 cancer cells (derived from gastric cancer) were implanted subcutaneously into the right flank of NSG mice. When tumors reached 70mm3, a single IV dose of 2M CAT-179 or control NK cells was administered. CAT-179 dosed animals showed a 96% durable tumor regression and significant survival benefit relative to animals dosed with control NK cells (p<0.0001). Efficacy strongly correlated with the circulating levels of CAT-179, which significantly infiltrated the tumor xenograft. Our pre-clinical results demonstrate the potential of CAT-179 as a novel, durable, and off-the-shelf cell therapy to overcome the challenges associated with solid tumors and provide quantitative insights into pharmacokinetics, pharmacodynamics and anti-tumor activity of engineered NK cells expressing CAR, TGFb DNR and IL-15.Citation Format: Bashar Hamza, Angela Nunez, Marilyn Marques, Alexia Barandiaran, Henry Moreno, Finola Moore, Meghan Walsh, Eugene Choi, Kisha Pradhan, Krista Daniel, Jennifer Johnson, Charlotte Franco, Andres Alvarez, Karl Malakian, Keith H. Wong, Joseph Gold, Vipin Suri, Dominic Picarella. CAT-179, an allogeneic NK cell product expressing HER2-CAR, IL-15 and TGFβ dominant negative receptor, durably regresses HER2-expressing xenograft tumors in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2904.

2023-04-04·Cancer Research

Abstract 2898: CAT-248, an allogeneic CD70-directed CAR-NK cell therapy effectively controls CD70-positive tumor xenografts

作者: Walsh, Meghan ; Pradhan, Kisha ; Alvarez, Andres ; Nguyen, Jenna ; Franco, Charlotte ; Gold, Joseph ; Hamza, Bashar ; Becker, Kelly ; Moore, Finola ; Malakian, Karl ; Picarella, Dominic ; Khurana, Priya ; Wong, Keith H. ; Moriarity, Branden S. ; Johnson, Jennifer ; Nunez, Angela ; Omobono, Mark A. ; Webber, Beau R. ; McAuliffe, Michele ; Chang, Jae-Woong ; Marques, Marilyn ; Moreno, Henry ; Blanco, Billy ; Rivera, Adriana ; Suri, Vipin ; Daniel, Krista ; Krueger, Joshua ; Thomas, Cherry ; Choi, Eugene ; Barandiaran, Alexia ; Marques, Beatriz

AbstractEngineered, off-the-shelf, allogeneic natural killer (NK) cell therapy is an attractive approach for targeting solid tumors, given their emerging clinical safety, efficacy, and intrinsic anti-tumor recognition and activity. However, improvements to support persistence and maintain durable anti-tumor activity within the tumor microenvironment may be necessary to achieve meaningful clinical efficacy. Here we describe the preclinical activity of CAT-248, a CD70-directed CAR-NK cell therapy, engineered using the TcBuster™ Transposon System (Bio-Techne) multiplexed with CRISPR/Cas9 editing. CD70 is highly expressed in many tumor types while normal tissue expression is restricted to a subset of activated immune cells. CAT-248 is an allogeneic, healthy donor peripheral blood-derived NK cell product designed for durable efficacy against CD70 expressing tumors. CAT-248 is engineered to express CD70 CAR, interleukin 15 (IL-15), and transforming growth factor β (TGFβ) dominant negative receptor (DNR). In addition, CAT-248 includes CRISPR/Cas9 knockout of CD70 to mitigate fratricide due to endogenous CD70 expression in activated NK cells. IL-15 enhances persistence of CAT-248 to enable durable efficacy, and TGFβ DNR enables CAT-248 to maintain high activity in TGFβ-enriched and immunosuppressive solid tumor microenvironments. CAT-248 is manufactured using transposon-based engineering which enables stable integration of the three transgenes and CRISPR/Cas9 knockout of CD70 in a single electroporation step, resulting in 40-80% CAR expression and 80-90% knockout of CD70 in CAT-248 NK cells. CAT-248 activity was characterized across a panel of in vitro assays to evaluate the function of CD70 CAR, TGFβ DNR, and IL-15 transgenes. CD70-directed cytotoxicity was assessed against a panel of tumor cell lines with a broad range of CD70 expression. In vitro, CAT-248 cells demonstrated both CAR-dependent cytotoxicity and over 2-fold greater secretion of effector cytokines IFNγ and TNFα than control NK cells. TGFβ DNR effectively prevented TGFβ-induced SMAD phosphorylation and TGFβ-induced downregulation of DNAM-1, an NK cell activating receptor. IL-15 secretion enabled in vitro NK cell expansion over a 9-day time course without exogenous cytokine support. To confirm cytolytic activity in vivo, CAT-248 cells were administered therapeutically in a 786-O CD70+ renal cell carcinoma xenograft model. CAT-248 cells effectively controlled tumor, demonstrating >99% reduction in tumor burden relative to control NK cells (p<0.01). Further, CAT-248 cells demonstrated significant in vivo persistence beyond 4 weeks post-dosing in peripheral blood. Overall, the results demonstrate the potential for CAT-248 as a novel off-the-shelf, cryopreserved, allogeneic NK cell therapy for CD70-positive renal cell carcinoma and other solid tumor malignancies.Citation Format: Bashar Hamza, Eugene Choi, Dominic Picarella, Finola Moore, Angela Nunez, Henry Moreno, Marilyn Marques, Alexia Barandiaran, Meghan Walsh, Kisha Pradhan, Krista Daniel, Kelly Becker, Jennifer Johnson, Karl Malakian, Keith H. Wong, Mark A. Omobono, Charlotte Franco, Andres Alvarez, Jenna Nguyen, Billy Blanco, Priya Khurana, Beatriz Marques, Adriana Rivera, Michele McAuliffe, Jae-Woong Chang, Joshua Krueger, Beau R. Webber, Branden S. Moriarity, Joseph Gold, Cherry Thomas, Vipin Suri. CAT-248, an allogeneic CD70-directed CAR-NK cell therapy effectively controls CD70-positive tumor xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2898.

2023-04-04·Cancer Research

Abstract 3191: Genetically modified TGF-β dominant negative receptor and IL15 enhance Natural Killer (NK) cell mediated cytolytic activity in glioblastoma

作者: Cruz, Conrad Russell ; Barron, Luke ; Bollard, Catherine ; Chaudhry, Kajal ; Suri, Vipin ; Muniraj, Nethaji ; Terao, Joshua Luke

AbstractIntroduction: Glioblastoma (GBM) presents with a poor prognosis and dismal survival rates. While cell-based immune therapies have shown success in other malignancies, there is currently little evidence that GBM is as responsive to current approaches. Novel therapies for these patients are therefore urgently needed. The antitumor effect may be limited by GBM’s rapid progression, its extensive intertumoral heterogeneity, and its immune suppressive microenvironment. For cell-based therapies to be effective, they need to be manufactured rapidly or in advance, recognize multiple targets on GBM, and resist immune suppression. We therefore sought to develop “off-the-shelf” cord blood-derived NK cell therapies capable of recognizing multiple stress ligands on tumor cells but are protected from the microenvironment by expression of a dominant negative receptor to TGFβ (abrogating the negative effects of the cytokine) and secretion of IL15 (overcoming negative signals from the microenvironment). We investigate the therapeutic efficacy of NK cells engineered to express IL15-and/or TGFβ-DNR in glioblastoma model in-vitro and in-vivo.Methods: NK cells were isolated from umbilical cord blood by magnetic selection, and subsequently modified to express IL-15, and/or TGFβ-DNR. Engineered NK cells were expanded with feeder cells. Retroviral transduction efficiency was confirmed by flow cytometry. IL15 expression was quantified by ELISA. To determine the cytotoxicity activity of our engineered NK cells against glioblastoma, we measured lysis of the U87MG cell line. To determine in vivo efficacy of our engineered NK cells, we used xenograft NSG mouse models that were orthotopically engrafted with U87MG in the brain. Tumor growth was measured by bioluminescence.Results: CAR-NK cells were successfully transduced (with a transduction efficiency ranging from 66-83% (mean 74.55% + 10.6, n>3) from umbilical cord blood. NK cells engineered to secrete IL15 secreted a mean of 288.3 pg/mL. After exposure to TGFβ in vitro, NK cells transduced with TGFβ-DNR had a increase of killing [mean 58.25 % + 4.51 at 20:1 (E:T) 48.57% + 11.55 without TGFβ, n=3] compared to un-transduced NK cells [mean 11.98 % + 4.51 at 20:1 (E:T) 49.04% + 5.34 without TGFβ, n=3]. Mice injected with IL15 and TGFβ DNR showed better control of tumor (3.99 x 105 + 0.0007 bioluminescence Vs 1.673 x 107 + 0.160 in mice given mock-transduced NK cells and 8.44 x 109 + 28.62 in control mice).Conclusion: Our preliminary results show that cord blood NK cells modified to secrete IL15 and express TGFβ-DNR can recognize and lyse GBM cells in vitro and orthotopically implanted GBM tumors in vivo.Citation Format: Nethaji Muniraj, Kajal Chaudhry, Joshua Luke Terao, Vipin Suri, Luke Barron, Catherine Bollard, Conrad Russell Cruz. Genetically modified TGF-β dominant negative receptor and IL15 enhance Natural Killer (NK) cell mediated cytolytic activity in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3191.

项与 Catamaran Bio, Inc. 相关的新闻（医药）

2024-09-17

·Pharmaceutical Technology

MaxCyte and Kamau Therapeutics sign platform license agreement

Kamau’s lead investigational programme, nula-cel, which is based on HDR editing, is currently in clinical development for sickle cell disease. Credit: Babul Hosen /Shutterstock. MaxCyte , a company specialising in cell engineering technologies, has entered a strategic platform licence (SPL) agreement with Kamau Therapeutics, a clinical-stage company focused on stem cell therapy gene correction, to speed up the development of cell therapeutics for genetic diseases. Kamau Therapeutics will gain non-exclusive research, clinical and commercial rights to utilise MaxCyte’s Flow Electroporation technology and ExPERT platform to support its homology-directed repair (HDR) novel gene correction technology. In exchange, MaxCyte will receive annual licensing fees along with programme-related revenue. Kamau’s approach to therapy development involves high-efficiency targeted gene integration, to build a new class of treatments to cure a range of serious and life-threatening diseases such as sickle cell disease (SCD). Its platform, based on HDR editing, builds upon first-generation CRISPR-Cas9 technology. This technique not only cuts DNA but also provides a DNA template. See Also: AstraZeneca’s Fasenra to challenge GSK’s Nucala in rare vasculitis after FDA nod FDA approves Accord BioPharma’s HERCESSI for cancer treatment MaxCyte CEO and president Maher Masoud stated: “Bringing this groundbreaking gene therapy research into the clinic requires a robust manufacturing process and the ability to scale. “By partnering with us, Kamau gains access to our commercially validated Flow Electroporation technology as well as technical, regulatory and scientific support. This enables them to optimise their clinical manufacturing process, mitigate risks and expedite the progression of their lead product candidate through clinical phases to deliver this potential cure to patients living with SCD.” Kamau co-founder Matthew Porteus said: “HDR overcomes prior limitations in specificity, efficiency and durability of gene editing to offer broad potential for transforming human health outcomes through the delivery of one-time curative cell therapies. “Through our collaboration with MaxCyte and the use of their proven non-viral platform, our goal is to treat or cure a range of serious genetic diseases with unmet medical needs using homology-directed repair.” Kamau’s lead investigational programme, nula-cel, which is based on HDR editing, is currently in clinical development for SCD. The ExPERT platform, MaxCyte’s electroporation technology, is designed to support the growing cell therapy market. It offers high transfection efficiency and scalability, which are critical for the production of next-generation cell-based therapeutics. The ExPERT platform includes products such as the ATx, STx, GTx, and VLx instruments, along with proprietary processing assemblies, disposables and software protocols, all backed by a global intellectual property portfolio. The link with Kamau is MaxCyte’s 29th clinical/commercial partnership. Each partnership typically generates pre-commercial milestone revenue, with a significant portion coming from programme-related revenue. In 2023, MaxCyte entered an SPL agreement with biotechnology company Catamaran Bio to support chimeric antigen receptor-NK cell therapy programmes.

引进/卖出细胞疗法基因疗法

2024-08-16

·药时代

单日暴涨88%，这家借壳上市医药公司为何受到资本青睐？

2024年7月，在生物医药领域，1家公司采取IPO形式上市，3家公司SPAC合并上市，3家公司反向并购上市。 IPO上市 7月，有1家医药公司采用IPO形式上市，融资规模为1.67亿美元。今年以来，生物医药领域已经有15家公司IPO上市，累计融资规模超23.5亿美元，其中不乏CG Oncology、Kyverna Therapeutics等IPO规模超3亿美元的公司。 1、Artiva(NASDAQ:ARTV) 6月7日，Artiva在纳斯达克交易所上市，发行价为美股12美元，发行1392万股，IPO规模达1.67亿美元，是今年第九家IPO规模超过1亿美元的创新药公司。 2021年，Artiva曾尝试进行IPO，但后来转而专注于与Affimed的合作。2023年10月，Artiva与默沙东高达10亿美元的合作终止，促使Artiva重新启动IPO计划。 Artiva Biotherapeutics是一家专注于开发基于自然杀伤（NK）细胞疗法的公司，主要产品候选物AlloNK®，是一种无需基因修饰的冷冻保存同种异体的NK细胞，可利用单克隆抗体（mAb）进行靶向。 Artiva建立了针对CAR-NK的研发平台，可为NK细胞装载了经过优化的CAR以增强其治疗活性和肿瘤靶向能力，能够保持CD16的高表达，联合单克隆抗体则可以实现双靶向治疗。为了生产AlloNK，Artiva选择具有CD16 158 V/V变异的脐带血，再基于生物反应器的大规模NK细胞扩增和活化过程以产生数千剂纯净的NK细胞，并保留CD16和其他肿瘤激活受体（如NKG2D、DNAM-1、NKp30、NKp46等）的高表达且一致表达的特征而无需额外的工程化处理，所产生的NK细胞经过优化的冷冻保存技术能够最大限度保证细胞活力，适应长距离物流运输，可以在门诊环境中重复给药。 Artiva可以使用不同的mAbs来靶向基于靶细胞抗原表达的不同B细胞群体。例如，CD19和CD20在记忆B细胞上表达，而CD38和BCMA在浆细胞上表达。在适应症的选择上，Artiva也跟随诸多细胞疗法公司进入自身免疫领域的浪潮，正在开展AlloNK®针对系统性红斑狼疮（SLE）和狼疮性肾炎（LN）的研究，管线包括： AB-101：一款脐带血来源、同种异体、冷冻保存、非转基因、ADCC（抗体依赖的细胞介导的细胞毒性作用）增强的NK细胞治疗候选药物，可在门诊与单克隆抗体或先天细胞接合剂联合使用。该疗法目前正处于临床I/II期试验中，与利妥昔单抗联合用于治疗狼疮肾炎（LN）、类风湿性关节炎（RA）、寻常型天疱疮（PV）、B细胞非霍奇金淋巴瘤（NHL）等适应症。 AB-201：一种新型HER2特异性CAR-NK细胞疗法，用于治疗HER2+实体瘤。公司计划在2022年提交IND申请。 AB-202：一种CD19特异性CAR-NK细胞疗法，用于治疗B细胞恶性肿瘤。公司同样计划在2022年提交IND申请。公司CEO Fred Aslan博士，在生物医药行业拥有20年丰富经验，曾担任Vividion Therapeutics的总裁兼首席财务官（被拜耳以20亿美元收购），亦曾在知名Biotech投资机构Venrock工作了12年，期间主导创立了Receptos Pharmaceuticals(被新基以70亿美元的价格收购)、Zeltiq(被艾尔建以20亿美元的价格收购)，并参与了Fate Therapeutics的组建。在一级市场，Artiva受到资本的追捧，进行了两轮融资： 2020年6月，公司完成了7800万美元的A轮融资。本轮融资由5AM Ventures,venBio Partners,RA Capital领投,Medivate Partners、GC LabCell等机构跟投； 2021年6月，公司宣布完成1.2亿美元B轮融资。本轮融资由Venrock领投，5AM Ventures, RA Capital、venBio Partners等机构跟投。不过，Artiva所在的CAR NK领域在近几个月却接连遭遇挫折，Caribou宣布削减临床前CAR-NK资产，裁员12%，而另一同行Catamaran Bio公司也在今年早些时候关闭。 SPAC上市 7月，生物医药领域有3家公司宣布或完成与SPAC公司的合并。 1、Adagio Medical(NASDAQ:ADGM) 7月31日，Adagio完成与SPAC公司ARYD的合并，该合并交易对Adagio的估值为1.13亿美元。在合并的同时，Perceptive Advisors、RA Capital、RTW Investments和ATW Partners等投资者已承诺为公司提供2000万美元的可转换债务和2200万美元的股权融资。 Adagio Medical公司由James Cox博士和Olav Bergheim先生于2011年创立，致力于开发新一代心脏心律失常导管消融技术，用于治疗心律失常，包括心房扑动、室性心动过速以及阵发性和持续性心房颤动。液氮作为一种强大的冷剂，在医疗器械中广泛应用，其中也包括冷冻消融领域。然而，液氮在从液态转变为气态时体积会急剧膨胀，这一缺陷限制了其在心内膜冷冻消融中的应用。自2004年以来，Adagio Medical的首席技术官Alex Babkin博士一直在深入研究和开发近临界氮气（NCN）冷冻消融技术，不仅克服了传统液氮冷冻剂在体积膨胀方面的问题，而且还保留了其作为冷冻剂的强大能力，能够创造持续性病变所需的稳定能量来源，为心内膜冷冻消融提供了一个创新的解决方案。此外，NCN的优点还包括： NCN的高冷却能力还为可伸缩技术提供了可能，使医生能够根据患者的具体情况进行个性化治疗； NCN的无蒸汽锁特性，还能够实现可靠的启动和停止控制，使得医生在治疗过程中能够更加精确地控制冷冻消融的范围和深度； NCN的低粘度特性使得它能够通过小导管（直径小于或等于9Fr）进行心内膜途径的冷冻消融，为心脏任何部位的长而连续病变的创造提供了可能。目前，公司正全力推进专有的超低温冷冻（ULTC）和脉冲场冷冻消融（PFCA）技术的临床试验计划，计划在2024年公布部分关键数据并推出新产品：超低温冷冻消融（ULTC）：该技术可通过连续的透壁病变，去治疗包括阵发性和持续性房颤、心房扑动和室性心动过速在内的心律失常,能够通过单一消融周期在心房和心室产生各种广泛的连续贯穿损伤。 2024年3月，ULTC获得CE标志批准，用于治疗单形室性心动速。由升级的冷冻消融控制台和vCLAS心室冷冻消融导管组成，冷冻消融控制台也能够支持使用商用iCLAS 导管。2024年5月，ULTC获得FDA批准，可针对室性心动过速和持续性房颤进行试验。脉冲场冷冻消融技术（PFCA）：该技术是ULTC和脉冲电场消融（PFA）的独特组合，共用一根导管，可以避免气泡，创造良好的组织接触，减少肌肉骨骼收缩，消融较深的病灶。结合了ULTC和PFA的优势，PFCA技术未来有可能成为心脏病治疗领域的重要突破。目前，PFCA技术正在欧洲进行试验。公司创始人兼CEO Olav Bergheim，亦是Fjord Ventures LLC的创始人和常务董事，此前Bergheim先生是Domain Associates的普通合伙人，负责多家公司的组建，包括3F Therapeutics(被美敦力收购);Vessix Vascular(被波士顿科学收购)，Volcano Therapeutics(被飞利浦收购)以及Glaukos(纳斯达克:GKOS)。在加入Domain之前，Bergheim先生在医疗器械巨头百特集团担任副总裁。公司最近一轮融资是2020年11月的E轮融资，融资规模达4250万美元，投资方包括ArrowMark, RA Capital、Perceptive、JMR Capital、 Fjord Ventures等机构。反向并购上市（Reverse Merger） 7月，共有3家生物医药公司宣布了反向并购上市。 1、Pieris(NASDAQ:PIRS) 7月25日，Pieris(NASDAQ:PIRS)宣布与Palvella Therapeutics合并，合并后的实体将作为Palvella运营，将继续在纳斯达克交易所上市，受此消息影响，Pieris股价当日暴涨88.6%。在宣布合并的同时，Pieris(NASDAQ:PIRS)获得7890万美元的PIPE融资，该融资由BVF Partners，Frazier Life Sciences领投，Blue Owl、Nantahala Capital、DAFNA Capital、ADAR1 Capital、Samsara BioCapital、Ligand(Nasdaq: LGND)等机构跟投，预计合并完成后的公司拥有8500万美元的现金。 Palvella的专有QTORIN™技术平台可以克服高分子量、化学和物理不稳定性、高药物浓度、有限的全身吸收等局部给药的局限性。此外，QTORIN™平台还可与多种药物兼容，用于靶向递送至病理部位，通常在表皮或真皮的深层内。目前，Palvella的主要在研药物是一款3.9%的雷帕霉素无水凝胶：QTORIN™ ，用于治疗微囊性淋巴畸形(微囊性LMs)、静脉畸形等适应症。微囊性淋巴管畸形是一种罕见的、慢性衰弱性遗传病，由PI3K/mTOR通路失调引起。该病以突出于皮肤屏障的局限性畸形淋巴管团，和持续漏出的淋巴液和出血为特征，此疾病经常导致患者反复严重感染和蜂窝织炎。该疾病目前没有获FDA批准的治疗方法。 2023年11月，FDA授予Qtorin雷帕霉素突破性疗法认定，该认定主要基于一项每日一次Qtorin雷帕霉素治疗微囊性淋巴管畸形的多中心、开放标签2期试验的积极结果。在该试验中，根据临床医生疗效总评量表的变化，100%接受Qtorin雷帕霉素治疗12周的受试者（n=12）被评定为“大幅改善”或“极大幅改善”。目前，Palvella正在开展一项关键性3期研究。除了突破性疗法认定，美国FDA此前还授予Qtorin雷帕霉素治疗微囊型淋巴管畸形的快速通道资格和孤儿药资格。欧洲药品管理局（EMA）也授予Qtorin雷帕霉素治疗微囊型淋巴管畸形的孤儿药资格。公司的首席科学官Shroot博士在皮肤疾病的药物研发方面拥有30多年的经验，并在Diffein、Atralin、Vethic和Diflucan等多个药物的开发中发挥了关键作用，是美国皮肤协会终身成就奖的获得者，也是皮肤病研究学会的终身荣誉会员。在一级市场，Palvella曾于2020年5月，完成4500万美元的C轮融资，投资方包括Samsara BioCapital，BVF Partners，Adams Street Partners，Opaleye Management，Ligand Pharmaceuticals等机构，并于2023年1月完成3770万美元D轮融资，投资方包括Petrichor、Gore Range Capital、Agent Capital、Nolan Capital、BioAdvance等机构。封面图来源：123rf 版权声明/免责声明本文为授权转载文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢! 药时代官方网站:www.drugtimes.cn 联系方式: 电话:13651980212 微信:27674131 邮箱:contact@drugtimes.cn 租金减免!创新基金!专业辅导!勃林格殷格翰邀您参赛股价暴涨220% ！“卖不动” 的CGT再成焦点一款长效激素疗法获批，以取代武田退市的甲状旁腺功能减退药物点击这里，发现价值信息！

细胞疗法IPO临床申请免疫疗法临床1期

2024-07-20

·药事纵横

诺奖得主公司Caribou：砍掉CAR-NK管线，裁员12%

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。 7月16日，Caribou Biosciences宣布将削减CAR-NK项目，将资源集中用于异体CAR-T细胞治疗平台，以及完成2024年和2025年的多个里程碑，快速推进四个肿瘤和自身免疫性疾病临床项目。此外公司宣布裁员21人，占公司员工总数的12%，公司预计在2024年第三季度末基本完成裁员。公司进行此次裁员是为了延长现金周转期，预计裁员及其他成本控制措施将使公司的现金流至少延长六个月，直至2026年下半年。在裁员方面，公司目前估计将产生约50万至10万美元的费用，主要包括现金遣散费、福利以及受影响员工的过渡支持服务。 Caribou的创始人之一为Jennifer Doudna，其与Emmanuelle Charpentier是最早于2012年公开发表CRISPR/Cas9研究成果的两个人，后二人在2020年获得诺贝尔化学奖。消失的CAR-NK管线个据官网曾经披露的管线资料可知此次削减的CAR-NK项目是CB-020。CB-020是一款诱导性多能干细胞 (iPSC) 衍生的同种异体抗ROR 1 CAR-NK细胞疗法，用于治疗实体瘤。Caribou Biosciences于2022年12月披露CB-020的靶点。倾尽家产开发细胞疗法该公司裁员、降低其他成本和削减CAR-NK项目的决定表明，要通过多年的临床试验成功推出一种新的细胞疗法，是多么的艰巨和昂贵。今年迄今，该公司市值已缩水52%，其股票$CRBU周二收盘价约为每股2.73美元，股价上涨28%。声明发布后，该公司股价在今日盘前交易中跌幅超过8%。初步未经审计的数据显示，截至2024年6月30日，Caribou预计拥有3.118亿美元的现金、现金等价物和有价证券，公司将于8月6日公布2024 H1业绩。截至2024年3月31日，Caribou拥有3.459亿美元的现金、现金等价物和有价证券，而截至2023年12月31日为3.724亿美元。 2024 Q1合并资产负债表（图源：官网）截至2024年3月31日的三个月内，Caribou的许可与合作协议收入为240万美元，而 2023年同期为350万美元。收入减少的主要原因是之前披露的艾伯维合作与许可协议现已终止，但Caribou于2023年6月29日与辉瑞公司签订的信息权协议确认的收入增加部分抵消了减少的收入。截至3月底，Caribou已累计亏损3.405亿美元，包括4120万美元的第一季度亏损。 2024 Q1合并损益表（图源：官网）将资金集中在最有可能迅速成功的项目上 Caribou正在采取大多数生物技术公司在经济低迷时期被迫做的事情：将资金集中在最有可能迅速成功的项目上。这家生物技术公司将把资源集中用于其现货型CAR-T 细胞疗法，即异体CAR-T细胞疗法。Caribou的三款CAR-T细胞疗法：CB-010治疗非霍奇金淋巴瘤，CB-011治疗多发性骨髓瘤和CB-012治疗急性髓系白血病-和CB-010治疗狼疮肾炎和肾外狼疮都处于早期阶段，开展I期临床试验中。最新研发管线（图源：官网） CB-010是Caribou公司的主要临床阶段候选异体CAR-T细胞疗法，CB-010利用基因编辑技术生成，除了表达靶向CD19的嵌合抗原受体，还利用基因编辑技术敲除了免疫检查点蛋白PD-1的表达，旨在提高抗肿瘤活性的持久性。 4月4日，Caribou Biosciences宣布同种异体CD19靶向CAR-T疗法CB-010的IND申请已经获得美国FDA的许可，用于治疗狼疮性肾炎（LN）和肾外狼疮（ERL）。预计CB-010治疗LN和ERL患者1期临床试验GALLOP将于2024年底前启动。 6月2日，Caribou在2024 年美国临床肿瘤学会 (ASCO) 年会公布了其同种异体CAR-T细胞疗法CB-010治疗复发/难治性B细胞非霍奇金淋巴瘤患者的新数据。正在进行的ANTLER第1阶段试验的最新临床数据表明，单剂量CB-010有可能与已获批准的自体CAR-T细胞疗法的安全性、有效性和持久性相媲美。在ANTLER中，共对46名患者进行了CB-010三种剂量水平（40x106、80x106和120x106 CAR-T细胞）的评估。在剂量增加过程中，16名多种亚型侵袭性复发或难治性B细胞非霍奇金淋巴瘤（r/r B-NHL）患者入组；30名二线大B细胞淋巴瘤（2L LBCL）患者入组。截至2024年4月1日的数据，CB-010的疗效和安全性可与已获批的自体CAR-T细胞疗法相媲美。13名部分人类白细胞抗原（HLA）匹配（≥4个等位基因）患者的总缓解率达92%，CR率为46%，中位无进展生存期（PFS）获得改善，为14.4个月。 CB-010 的耐受性总体良好。没有观察到3级或更高的细胞因子释放综合征（CRS）和移植物抗宿主病（GvHD）。 CAR-NK公司共同面临的困境基于CAR-NK疗法的研究目前处于起步阶段，距离成药验证还有很长一段路要走，伴随波折的发展历程，Caribou和其他CAR-NK生物技术公司也面临许多挑战。 2023年9月26日，艾伯维 (AbbVie) 已终止与Caribou共同开发两款新靶点的通用CAR-T疗法的合作。艾伯维表示这是基于公司的战略重点决定的。2021年，AbbVie向这家初创公司预付了4000万美元，并承诺为两款新靶点的通用性CAR-T疗法提供高达3亿美元的研发和注册里程碑金额。 CAR-NK疗法开发商Artiva与默沙东的合作已经于2023年10月结束。早在2021年1月28日，Artiva宣布公司与默沙东签订了全球独家合作和许可协议。默沙东支付了3000万美元的预付款，以及未来可能付出数倍于该价格的里程碑付款。根据当时条款，除了Artiva获得的前两个项目3000万美元外，如果Merck决定选择第三个项目，还将额外支付1500万美元。根据未来的发展、商业化里程碑和产品的全球销售，Artiva有可能每个项目获得高达6.12亿美元。 Artiva的合作伙伴 Affimed裁员达50%，Affimed表示裁员是为了节约资金，专注于其3个NK细胞疗法临床项目的研发。与此同时，现货型CAR-NK生物技术公司 Catamaran Bio于今年早些时候倒闭。在更广泛的NK细胞治疗领域，百济神州于2月放弃了与Shoreline Biosciences 的合作。 CAR-NK疗法仍极具前景 NK细胞在抗肿瘤方面起着重要作用，临床前及临床研究结果均揭示了CAR-NK细胞具备较好的杀伤血液瘤和实体瘤细胞的功能，相比于CAR-T细胞，两者CAR结构相似，但CAR-NK细胞具有更强的肿瘤杀伤毒性，且不易引起 GVHD、CRS 等不良反应，随着NK细胞生物学和转化研究领域的不断进展，目前CAR-NK疗法的临床研究的数量逐年增加。国外布局NK细胞疗法的企业中进展较快的Celularity、Nkarta、Fate、Artiva等已先后迈入1期临床，多个候选药物已经在临床前或IIT中验证了基本的安全性和有效性。国内约有31家布局NK/CAR-NK细胞疗法的企业，研发阶段均处于早期。在研究的靶标方面，CD19抗原在血液肿瘤中最常见。在实体瘤中进展最为广泛的CAR-NK疗法包括肿瘤相关抗原HER2、MUC1和PMSA等靶点。相信在不久的将来，NK/CAR-NK疗法将在多种领域中展现其潜力，为患者带来更多治疗选择。参考资料： [1]公司官网 [2]https://endpts.com 往期文章：国内31家NK/CAR-NK企业管线梳理

细胞疗法基因疗法免疫疗法临床研究

100 项与 Catamaran Bio, Inc. 相关的药物交易

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100 项与 Catamaran Bio, Inc. 相关的转化医学

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