UB-VV111

Umoja Biopharma是一家创立于 2019 年、总部位于美国华盛顿州西雅图的临床阶段生物制药公司，专注于开发创新的体内（in vivo）CAR-T 细胞疗法与免疫肿瘤学“即用型”综合平台。其核心技术旨在克服传统体外（ex vivo）CAR-T 疗法耗时长、成本高昂和流程复杂的瓶颈。 截至2026年中，该产品处于早期临床开发阶段（Phase 1），尚未进入后期申报（如BLA），但已获得FDA IND clearance（2024年7月，首个in vivo CAR-T IND获批）和Fast Track Designation（2025年9月，用于经≥2线治疗后的r/r LBCL和CLL）。 以下从CMC、非临床、临床、监管策略及整体申报角度进行系统解读，基于企业公告、ClinicalTrials.gov（NCT06528301）、ASH poster等公开信息。 产品机制与平台概述（核心创新点） UB-VV111是一种第三代、自灭活、复制缺陷的慢病毒载体（LVV）药物产品，属于off-the-shelf基因治疗产品。 关键组件 表面工程化包膜（含cocal病毒融合糖蛋白 + 膜结合多域融合蛋白MDF，包括 CD58、CD80和抗CD3 scFv），提供T细胞趋向性和激活信号；携带转基因（抗CD19 CAR + Rapamycin-Activated Cytokine Receptor, RACR™系统）。作用机制静脉（IV）或淋巴结内（IN）给药后，选择性转导T细胞，在体内生成表达CD19 CAR和RACR的CAR-T细胞。RACR允许通过口服rapamycin选择性扩增/富集这些CAR-T细胞，无需化疗淋巴细胞清除（lymphodepletion）。优势无需患者白细胞分离术（apheresis）、个性化制造，缩短周转时间（即时给药），潜在降低成本，扩大患者可及性；适用于CAR-T naïve和prior CAR-T暴露患者。 这与传统ex vivo CAR-T（如axi-cel、tisa-cel）形成显著差异，是申报中的核心差异化点。 2. CMC（Chemistry, Manufacturing, and Controls） Umoja在科罗拉多州Louisville拥有先进的LVV开发和制造设施，支持平台化生产。 LVV开发通常指生物医药领域的慢病毒载体（Lentiviral Vector, LVV）工艺开发，广泛应用于CAR-T和基因治疗。它主要涵盖上游悬浮/贴壁培养、下游澄清纯化以及分析方法开发三个核心环节。 制造特点 off-the-shelf LVV药物产品，批次规模化生产（非患者特异性），符合基因治疗CMC要求（病毒载体纯度、滴度、杂质控制、稳定性等）。VivoVec平台强调表面工程化以实现T细胞选择性。 VivoVec平台通过在慢病毒颗粒表面展示多域融合配体（MDF）来替代传统假型化，精准靶向T细胞表面的CD8/CD3等分子并传递TCR激活信号，从而实现体内T细胞的高特异性选择和高效转导。监管关注点FDA对LVV产品的重点包括载体整合安全性（insertional mutagenesis风险）、复制能力（RCR检测）、转导效率和产品一致性。非临床数据显示低VCN（vector copy number，均值~1.77，<5）和典型LV整合位点谱，与已批准ex vivo LV-CAR-T相当。申报准备IND阶段已提供充分CMC数据支持clearance。未来BLA需完整商业化制造工艺验证、过程/产品表征、稳定性数据和comparability研究。平台化特性利于多适应症扩展，但需证明不同批次/剂型的一致性。 总体CMC路径相对ex vivo CAR-T简化（无需个性化细胞加工），但需加强病毒载体特有安全性数据。 3. 非临床（Nonclinical）支持（毒理、药代、药效） ASH 2024 poster提供了全面GLP非临床数据包，支持IND和临床推进。 药效 体外/体内研究显示选择性T细胞转导、CD19特异性杀伤、细胞因子分泌和增殖；rapamycin增强扩增。CD34-人源化小鼠和犬模型中观察到CAR-T生成、B细胞清除和抗肿瘤活性，无需淋巴细胞清除（lymphodepletion）。毒理与生物分布13周GLP毒理研究（CD34-人源化NSG小鼠，IV/IP给药+rapamycin）耐受性良好，无相关死亡、体重/临床/血液/生化/组织病理学不良发现。载体RNA快速清除（IV给药后2h剩余<5%）；转导主要限于免疫细胞，低off-target（非淋巴组织罕见，犬模型中非淋巴组织无量化转导）。巨噬细胞转导在小鼠模型中罕见，人原代细胞研究支持低风险。致癌/整合风险低VCN和整合谱支持与批准LV产品相当的风险水平；无插入致癌高风险证据。其他支持IN和IV两种给药途径独立剂量递增。IN（鼻内给药，Intranasal）和IV（静脉注射，Intravenous）是两种不同的药物输送方式） 这些数据为IND提供了坚实基础，强调安全性窗口，降低了FDA对新型in vivo递送的担忧。未来需补充更长期致癌性评估（如果必要）和临床前-临床转化数据。 4. 临床试验设计与数据（安全性和有效性） UB-VV111-01 (INVICTA-1, NCT06528301)：全球、多中心、开放标签Phase 1剂量递增+确认研究（启动2025年3月，首例预计2025年底，计划招募106例）。 目标人群     成人r/r LBCL（复发/难治性大B细胞淋巴瘤）或CLL/SLL（慢性淋巴细胞白     血病/小淋巴细胞淋巴瘤）（≥2线治疗后），可测量疾病（Lugano 2014或iw      CLL 2018），ECOG 0-1，无异基因移植史；包括CAR-naïve和prior CAR-     T暴露患者（需确认CD19表达）。设计BOIN（Bayesian optimal interval）设计，独立评估IN和IV途径，± rapamycin臂。单剂UB-VV111 + rapamycin方案。主要目标 安全性（AE发生率、剂量限制毒性）、MTD/MAD、RP2D。次要/探索 初步抗肿瘤活性（ORR、缓解持续时间）、PK/PD（CAR-T扩增、B细胞耗竭）、生物标志物。 随访 最长2年安全性随访。 当前状态：招募中，无公开中期疗效/安全性数据（截至最新公开信息）。Fast Track基于非临床和早期潜力授予，强调未满足需求。 安全性关注：潜在CRS/ICANS（CAR-T相关）、插入相关风险、rapamycin不良反应、off-target转导。非临床支持低风险，但临床需密切监测（尤其是首次人体）。  有效性：目标是显示可比或优于现有CAR-T的ORR/CR率和持久性，尤其在prior CAR-T失败患者中。in vivo生成可能带来独特PD特征（持续生成/扩增）。 Phase 1数据成熟后，可能快速进入Phase 2（Fast Track支持滚动审查、频繁互动）。 5. 监管策略与里程碑FDA IND Clearance（2024.7）：首个in vivo CAR-T IND，标志性成就。Fast Track Designation（2025.9）：针对特定r/r LBCL和CLL适应症，便利开发与审查（滚动BLA、加速批准潜力）。合作：AbbVie有CD19 in vivo CAR-T候选物独家许可选择权（潜在大额交易）。其他：美国为主，全球多中心试验；无公开NMPA/EMA信息（中国申报需单独桥接/本地数据）。 申报路径展望：短期 完成Phase 1，确定RP2D，申请RMAT（若符合突破性）或突破性疗法指定。中期 pivotal Phase 2/3，针对r/r LBCL/CLL，使用ORR作为加速批准终点（常见于细胞/基因治疗），OS/PFS确证。挑战 长期安全性（整合致癌、持久CAR-T）、制造规模化、患者异质性（prior therapy影响）。优势 off-the-shelf + 无lymphodepletion简化方案，Fast Track加速；平台可扩展至其他靶点/适应症（含自身免疫）。 6. 整体评估与风险 积极因素：创新机制解决真实临床痛点，非临床数据扎实，监管里程碑领先同类in vivo产品，企业融资与合作支持。 风险与不确定性：Phase 1早期，疗效/安全性数据待验证；in vivo递送的独特风险（系统分布、不可控转导）；竞争激烈（ex vivo CAR-T已建立标准）；CMC商业化放大挑战。 申报前景：作为平台首款资产，若Phase 1显示良好安全性+初步活性，有望加速路径至批准，潜在重塑B细胞恶性肿瘤治疗格局。但需持续生成高质量临床数据支持BLA。 参考资料 Brandes, A. H., Soo Min Koo, A., Perez, A., Michels, K., Friesen, T., Sheih, A., Parilla, D., Hernandez, S. A., Ericson, N., Dickerson, S., Muhonen, M., Freeman, J., Gould, S., Sullivan, S. M., Teoh, J., Ryu, B., Scharenberg, A. M., & Larson, R. P. (2024). Nonclinical toxicology, biodistribution, and pharmacokinetics of UB-VV111, an in vivo anti-CD19 CAR T cell therapy [Abstract 2046]. *Blood, 144*(Suppl 1). https://doi.org/10.1182/blood-2024-2046 (or ASH annual meeting abstract) Garcia, J., Dehner, C., Teoh, J., Brandes, A., & Wallis, W. (2024). A Phase 1, multicenter, open-label study of UB-VV111 in combination with rapamycin in relapsed/refractory CD19+ B-cell malignancies (INVICTA-1) [Abstract 1750.1]. *Blood, 144*(Suppl 1). https://doi.org/10.1182/blood-2024-1750.1 (or ASH annual meeting abstract) OncLive. (2025, September 30). *FDA grants Fast Track designation to UB-VV111 for R/R B-cell malignancies*. https://www.onclive.com/view/fda-grants-fast-track-designation-to-ub-vv111-for-r-r-b-cell-malignancies Pharmaphorum. (2025). *Umoja’s in vivo cell therapy fast-tracked by FDA*. https://pharmaphorum.com/news/umojas-vivo-cell-therapy-fast-tracked-fda Targeted Oncology. (2024, July 31). *FDA clears IND application of UB-VV111 in hematologic malignancies*. https://www.targetedonc.com/view/fda-clears-ind-application-of-ub-vv111-in-hematologic-malignancies Umoja Biopharma. (2024, July 31). *Umoja Biopharma announces FDA clearance of IND application for UB-VV111, a CD19 directed in situ CAR T for hematologic malignancies* [Press release]. https://www.umoja-biopharma.com/news/umoja-biopharma-announces-fda-clearance-of-ind-application-for-ub-vv111-a-cd19-directed-in-situ-car-t-for-hematologic-malignancies Umoja Biopharma. (2025, September 30). *Umoja Biopharma announces that UB-VV111 receives FDA Fast Track designation for relapsed/refractory B-cell malignancies* [Press release]. https://www.umoja-biopharma.com/news/umoja-biopharma-announces-that-ub-vv111-receives-fda-fast-track-designation-for-relapsed-refractory-b-cell-malignancies U.S. National Library of Medicine. (2024–2026). *A Phase 1 study of UB-VV111 with and without rapamycin in relapsed/refractory CD19+ B-cell malignancies* (ClinicalTrials.gov Identifier NCT06528301). https://clinicaltrials.gov/study/NCT06528301 免责声明 本文所载信息均整理自公开可查的官方公告、企业披露及行业媒体，截至发稿前力求准确。本文仅供科普参考，不构成任何医疗建议或购买决策依据。如有具体治疗需求，请咨询专业医师。

iStock, Alina Vytiuk Safety will be the key determinant of in vivo CAR T therapies, according to H.C. Wainwright’s Mitchel Kapoor, who noted that convenience and efficacy won’t be enough to impress investors in this space. Eli Lilly, AbbVie, AstraZeneca and more are up for the challenge. Cell therapies have already proven their worth in the clinic, effectively turning the body’s immune system against cancer—and soon, potentially autoreactive immune cells, too. But manufacturing and cost challenges continue to plague the modality, keeping it out of reach of many patients who need it. Enter in vivo CAR T therapy. Currently, CAR T therapies are produced ex vivo, or outside the body. A patient’s T cells are harvested and engineered in a lab to turn them into cancer killers. These new cells are then allowed to multiply before being injected back into the patient. An in vivo approach, meanwhile, enables the generation of CAR T cells inside the patient’s body. This technology “can fundamentally change how healthcare practitioners administer cell therapy,” Mitchell Kapoor, senior biotech equity research analyst at H.C. Wainwright, told BioSpace in an email. “It could shorten time to infusion, cut the cost of cell therapy, and ultimately broaden access to hundreds of thousands of patients,” he said. ezstandalone.cmd.push(function () { ezstandalone.showAds(129); }); The ex vivo track was validated by Novartis’ Kymriah when it became the first CAR T therapy to win the FDA’s approval in 2017 , paving the path for other medicines like Bristol Myers Squibb’s Breyanzi and Gilead’s Yescarta. The problem with ex vivo CAR T is access, Kapoor said. “What it doesn’t do is scale,” he continued, adding that the process is time-consuming and expensive, and is often limited by the capabilities of the clinics dispensing the therapies. In vivo CAR T, which involves delivering a piece of DNA into cells and transforming them into cancer-killers inside the body, circumvents these issues, explained Kostas Biliouris, managing director at Oppenheimer. Such an approach, Biliouris said, eliminates the need to initially extract cells from patients and the preconditioning chemotherapy required to prevent an immune reaction to the implanted CAR T constructs, making for an overall shorter and smoother experience. “In a sense, the body becomes the manufacturing site,” Kapoor added. For all its potential upside, however, there remains a key question at the heart of in vivo CAR T therapy: safety. “Moving manufacturing into the patient solves access and cost, but it takes the most complicated step—engineering the cells—out of a facility you can inspect and moves that process, and its quality control, into a patient who you can’t inspect,” Kapoor said. An ex vivo approach gives companies high levels of control over their product, but with in vivo, “once the vector’s in, you’re committed,” he cautioned. Companies that can demonstrate precision and control even while inside the body will rise to the top of the field, Kapoor said, adding, “Convenience and efficacy won’t be enough to wow investors unless safety is pristine.” Still, if this challenge can be solved, the allure of in vivo is strong for the pharma industry, which stands to gain a scalable therapeutic modality that lowers manufacturing costs while also expanding adoption to a broader market, Biliouris said. This has led to what he called “growing FOMO”—fear of missing out—among large biopharma companies, he continued. Indeed, the past two years have seen high-pro big-ticket deals in this space as industry giants, including Eli Lilly, AbbVie and AstraZeneca try to secure exposure to what Biliouris said could become the next major cell therapy platform. Lilly leads space with deal spree Arguably the biggest mover in the in vivo CAR T arena this year is Lilly, which in February paid $2.4 billion to acquire Orna Therapeutics, getting a clinical trial-ready asset that the pharma plans to develop for B cell–driven autoimmune diseases. Orna’s design engine leverages circular RNA molecules, delivered using a lipid nanoparticle, to enable patients’ bodies to produce their own CAR T cells. Such an approach has shaken Lilly’s long-standing skepticism toward the CAR T space. In a 2019 interview with Reuters , Lilly CEO David Ricks called the data behind CAR T therapy “amazing” but lamented that “practically, it’s not reaching many people.” Much of this apprehension, it turns out, was focused on ex vivo CAR T, which is “complex, confusing, inconvenient for patients,” a spokesperson told BioSpace in an email. “As a result of these complexities, only a fraction of patients who are eligible for ex vivo CAR-T therapies actually end up receiving them.” An in vivo approach bypasses these problems, the spokesperson added, minimizing wait times and eliminating the need for additional infrastructure that ex vivo therapies otherwise require. In vivo CAR T, if successful, “could bring a therapy that’s currently out of reach to far more patients.” The Indiana giant followed up its Orna buy with the up to $7 billion pickup of Kelonia Therapeutics in April. The deal, which as of publication has yet to close, will give Lilly the lentiviral KLN-1010, which targets the BCMA protein to treat multiple myeloma. At ASCO 2026, data from the Phase 1 inMMyCAR study showed a 100% overall response rate in all 18 patients treated with KLN-1010, with bone marrow samples testing negative for minimal residual disease at one month after treatment. Four patients who had been followed for at least four months showed no signs of disease. Mergers & acquisitions Lilly adds gene delivery technology to CAR T in up to $7B Kelonia deal After entering the CAR T space in February, Eli Lilly is “jumping into in vivo CAR-T with both feet” with the acquisition of Kelonia Therapeutics and its gene delivery technology. April 20, 2026 · 2 min read · Annalee Armstrong Read more Legend stands among giants A standout on this list is Legend Biotech, which is ushering an in vivo CAR T asset through the clinic without the typical deep pockets and entrenched infrastructure of Big Pharma. Legend’s candidate LB2501 targets both the CD19 and CD20 proteins found on B cells. The therapy, which is designed to enable the patient to produce their own CAR T cells after a single intravenous infusion, is in Phase 1 testing for relapsed or refractory B cell malignancies. Phase 1 data disclosed last month demonstrated a 100% response rate in patients with non-Hodgkin lymphoma (NHL)—findings that “point to a potentially best-in-class pro the in vivo CART space and best-in-disease pro NHL,” Oppenheimer analysts told investors in a June 2 note. LB2501 also had an overall favorable safety profile, with no documented cases of deaths, serious adverse events or dose-limiting toxicities. Overall, the asset’s Phase 1 performance “strengthens chances” of Legend being acquired, Oppenheimer added, pointing to the Lilly acquisitions as sign that in vivo CAR T is becoming “a very active M&A space.” LB2501’s Phase 1 study is ongoing with a primary completion date in mid-2027. Legend inked a CAR T collaboration with Johnson & Johnson in 2017, and together the companies developed the ex vivo therapy Carvykti. It won its first FDA approval in February 2022 , for relapsed or refractory multiple myeloma. “We view in vivo CAR-T as a natural extension of our leadership in cell therapy” and a key next step in the cancer field, Legend CEO Ying Huang told BioSpace over email. Legend’s early clinical findings for LB2501, Huang added, “reinforce our belief that in vivo approaches have the potential to complement existing cell therapy modalities.” CAR-T Legend soars on ‘best-in-class,’ ‘best-in-disease’ in vivo CAR T in early lymphoma study All six non-Hodgkin lymphoma patients on Legend Biotech’s CAR T therapy responded to treatment—findings that could make the biotech an attractive takeover target, according to analysts at Oppenheimer. June 3, 2026 · 2 min read · Tristan Manalac Read more AbbVie, the early believer Illinois-based AbbVie was an early believer in the promise of in vivo CAR T therapies. The pharma in January 2024 bet up to $1.4 billion in a pair of deals to partner with Umoja Biopharma, gaining access to the biotech’s VivoVec platform, which uses a lentiviral vector to deliver a gene construct that allows the patient’s body to produce its own CAR T cells. The main asset under the collaboration is UB-VV111, a CD19-targeting in vivo candidate in Phase 1 development for B cell cancers driven by the mutation. The study is recruiting participants with a primary completion date in March 2029. In the second deal, AbbVie secured the option to leverage VivoVec for up to four other in vivo CAR T candidates. But AbbVie wasn’t done. In June 2025, the company made another hefty investment in its in vivo CAR T portfolio, earmarking up to $2.1 billion to acquire Capstan Therapeutics. Capstan’s tech uses lipid nanoparticles to deliver RNA molecules that can reprogram the patient’s cells to produce CAR T constructs. The biotech’s lead asset was CPTX2309, which has since been renamed ABBV-619 and is in Phase 1 development for B cell–mediated autoimmune diseases. Business AbbVie Inks Two CAR-T Deals Worth Up to $1.4B with Umoja, Targets Multiple Cancers The two agreements announced Thursday will allow AbbVie to leverage Umoja Biopharma’s VivoVec delivery platform, which enables patients’ cells to produce their own cancer-fighting CAR-T cells. January 5, 2024 · 2 min read · Tristan Manalac Read more Death clouds AstraZeneca’s path Like AbbVie, AstraZeneca entered the in vivo CAR T space by acquiring a smaller developer with promising tech. In March 2025, the company picked up Belgium-based EsoBiotec and its proprietary ENaBL platform that enables the in vivo programming of immune cells, retooling them to target and attack tumors or self-targeting cells in autoimmune disease. ENaBL allows cell therapies “to be administered through a simple [intravenous] injection” and eliminates the need for the usual immune depletion preparatory step, AstraZeneca said at the time. For this bounty, the pharma paid $425 million upfront plus the possibility of $575 million more in milestones. That investment has started to pay off. Phase 1 data published in Nature Medicine in March showed that an investigational in vivo asset, dubbed ESO-T01, eradicated cancer in three of five enrolled patients with relapsed or refractory multiple myeloma. Four of the treated participants responded to the cell therapy and tested negative for minimal residual disease at 60 days. One patient died, however, after grade 1 immune effector cell-associated neurotoxicity (ICANS), a severe complication associated with cancer immunotherapies in which immune cells attack and damage neurons. The study wasn’t sponsored by AstraZeneca. “Every death on a trial is a tragedy,” a company spokesperson told BioSpace over email. Patients enrolled in the early-stage study were refractory to prior treatments, had aggressive disease and had relapsed several times, the spokesperson continued, adding that the ESO-T01 study showed that an in vivo approach is “feasible without lymphodepletion.” “AstraZeneca is now working to further develop in vivo treatments based on these results,” the spokesperson said.