A Phase 1/2, First-in-Human, Open Label, Dose Escalation and Expansion Study of AU-007, A Monoclonal Antibody That Binds to IL-2 and Inhibits IL-2Rα Binding, in Patients With Unresectable Locally Advanced or Metastatic Cancer

This is a first in human, open-label, multi-center Phase 1 / 2 study to evaluate the safety, tolerability, and initial efficacy of AU-007 in patients with advanced solid tumors. AU-007 will be administered either as a monotherapy, or in combination with a single loading dose of aldesleukin, or with both AU-007 and aldesleukin given every 2 weeks (Q2w). Once the recommended phase 2 dose (RP2D) of AU-007 plus aldesleukin was determined, (AU-007 Q2w plus a single loading dose of aldesleukin), AU-007 plus aldesleukin is also being administered with avelumab or nivolumab.

开始日期2022-04-04

申办/合作机构

Aulos Bioscience, Inc.

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项与 Imneskibart 相关的文献（医药）

2023-12-01·Acta obstetricia et gynecologica Scandinavica

Prevention of fetal brain injury in category II tracings

Article

作者: Nakao, Masahiro ; Nakai, Akihito ; Tamiya, Nanako ; Suzuki, Hideaki ; Ross, Michael G. ; Ikeda, Tomoaki ; Satoh, Shoji ; Fujimori, Keiya ; Toyokawa, Satoshi ; Ichizuka, Kiyotake ; Iwashita, Mitsutoshi ; Oka, Akira ; Magawa, Shoichi ; Kanayama, Naohiro ; Maeda, Tsugio

Abstract:

Introduction:

With category II fetal heart rate tracings, the preferred timing of interventions to prevent fetal hypoxic brain damage while limiting operative interventions remains unclear. We aimed to estimate fetal extracellular base deficit (BDecf) during labor with category II tracings to quantify the timing of potential interventions to prevent severe fetal metabolic acidemia.

Material and methods:

A longitudinal study was conducted using the database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy, including infants with severe cerebral palsy born at ≥34 weeks' gestation between 2009 and 2014. Cases included those presumed to have an intrapartum onset of hypoxic–ischemic insult based on the fetal heart rate pattern evolution from reassuring to an abnormal pattern during delivery, in association with category II tracings marked by recurrent decelerations and an umbilical arterial BDecf ≥ 12 mEq/L. BDecf changes during labor were estimated based on stages of labor and the frequency/severity of fetal heart rate decelerations using the algorithm of Ross and Gala. The times from the onset of recurrent decelerations to BDecf 8 and 12 mEq/L (Decels‐to‐BD8, Decels‐to‐BD12) and to delivery were determined. Cases were divided into two groups (rapid and slow progression) based upon the rate of progression of acidosis from onset of decelerations to BDecf 12 mEq/L, determined by a finite‐mixture model.

Results:

The median Decels‐to‐BD8 (28 vs. 144 min, p < 0.01) and Decels‐to‐BD12 (46 vs. 177 min, p < 0.01) times were significantly shorter in the rapid vs slow progression. In rapid progression cases, physicians' decisions to deliver the fetus occurred at ~BDecf 8 mEq/L, whereas the “decisions” did not occur until BDecf reached 12 mEq/L in slow progression cases.

Conclusions:

Fetal BDecf reached 12 mEq/L within 1 h of recurrent fetal heart rate decelerations in the rapid progression group and within 3 h in the slow progression group. These findings suggest that cases with category II tracings marked by recurrent decelerations (i.e., slow progression) may benefit from operative intervention if persisting for longer than 2 h. In contrast, cases with sudden bradycardia (i.e., rapid progression) represent a challenge to prevent severe acidosis and hypoxic brain injury due to the limited time opportunity for emergent delivery.

2018-01-01·Journal of enzyme inhibition and medicinal chemistry2区 · 医学

Selectivity analyses of γ-benzylidene digoxin derivatives to different Na,K-ATPase α isoforms: a molecular docking approach

2区 · 医学

ArticleOA

作者: Blanco, Gustavo ; Villar, José A. F. P. ; Barbosa, Leandro A. ; Alves, Silmara L. G. ; Pessôa, Marco T. C. ; Taranto, Alex G.

Digoxin and other cardiotonic steroids (CTS) exert their effect by inhibiting Na,K-ATPase (NKA) activity. CTS bind to the various NKA isoforms that are expressed in different cell types, which gives CTS their narrow therapeutic index. We have synthesised a series of digoxin derivatives (γ-Benzylidene digoxin derivatives) with substitutions in the lactone ring (including non-oxygen and ether groups), to obtain CTS with better NKA isoform specificity. Some of these derivatives show some NKA isoform selective effects, with BD-3, BD-8, and BD-13 increasing NKA α2 activity, BD-5 inhibiting NKA α1 and NKA α3, BD-10 reducing NKA α1, but stimulating NKA α2 and α3; and BD-14, BD-15, and BD-16 enhancing NKA α3 activity. A molecular-docking approach favoured NKA isoform specific interactions for the compounds that supported their observed activity. These results show that BD compounds are a new type of CTS with the capacity to target NKA activity in an isoform-specific manner.

2004-03-01·Biosensors & bioelectronics1区 · 工程技术

Low-level detection of a Bacillus anthracis simulant using Love-wave biosensors on 36°YX LiTaO3

1区 · 工程技术

Article

作者: Branch, Darren W. ; Brozik, Susan M.

We present an acoustic Love-wave biosensor for detection of the Bacillus anthracis simulant, Bacillus thuringiensis at or below inhalational infectious levels. The present work is an experimental study of 36 degrees YX cut LiTaO3 based Love-wave devices for detection of pathogenic spores in aqueous conditions. Given that the detection limit (D1) of Love-wave-based sensors is a strong function of the overlying waveguide, two waveguide materials have been investigated, which are polyimide and polystyrene. To determine the mass sensitivity of Love-wave sensor, bovine serum albumin (BSA) protein was injected into the Love-wave test cell while recording the magnitude and phase shift across each sensor. Polyimide had the lowest mass detection limit with an estimated value of 1.0-2.0 ng/cm2, as compared to polystyrene where D1 = 2.0 ng/cm2. Suitable chemistries were used to orient antibodies on the Love-wave sensor using protein G. The thickness of each biofilm was measured using ellipsometry from which the surface concentrations were calculated. The monoclonal antibody BD8 with a high degree of selectivity for anthrax spores was used to capture the non-pathogenic simulant B. thuringiensis B8 spores. Bacillus subtilis spores were used as a negative control to determine whether significant non-specific binding would occur. Spore aliquots were prepared using an optical counting method, which permitted removal of background particles for consistent sample preparation. This work demonstrates that Love-wave biosensors are promising for low-level detection for whole-cell biological pathogens.

项与 Imneskibart 相关的新闻（医药）

2025-04-29

·Business Wire

Aulos Bioscience Presents New Phase 2 Data for AU-007 Demonstrating Continued Strong Anti-Tumor Activity in Advanced Cancers at AACR Annual Meeting

LARKSPUR, Calif.--(BUSINESS WIRE)--Aulos™ Bioscience, an immuno-oncology company working to revolutionize cancer care through development of its lead immune-activating antibody therapeutic, today presented positive results from its Phase 1/2 dose escalation and cohort expansion study of its investigational candidate AU-007. The data were shared in a poster presentation at the American Association for Cancer Research (AACR) Annual Meeting in Chicago, Illinois. The interim Phase 2 data demonstrate clear evidence of durable partial and complete tumor response in multiple cancer types, including patients with melanoma whose tumors had progressed through prior checkpoint inhibitors and who received a combination of AU-007 and low-dose, subcutaneous aldesleukin. Durable tumor shrinkages were also observed in patients with checkpoint inhibitor-resistant or progressed renal cell carcinoma (RCC) who received the same AU-007 and aldesleukin regimen. Additionally, AU-007 and low-dose, subcutaneous aldesleukin continues to demonstrate a unique pharmacodynamic (PD) profile in the interleukin-2 (IL-2) class, with regulatory T cells (Tregs) decreasing and CD8 effector T cells expanding at all AU-007 dose levels. “We are very pleased with the clinical activity observed with AU-007 and low-dose, subcutaneous aldesleukin without a checkpoint inhibitor, as it accentuates our confidence in AU-007 as a potential best-in-class therapeutic for multiple cancers,” said Aron Knickerbocker, Aulos Bioscience’s president and chief executive officer. “Deep and durable tumor shrinkages, including complete responses, are occurring in patients who were refractory to treatment and had achieved no responses from highly potent prior immuno-oncology regimens. Importantly, the results reinforce the previously reported observation that the CD8 effector T cell expansion and Treg reduction correlates with clinical efficacy. This key driver of Treg reduction coupled with CD8 effector T cell expansion and enhancement of the CD8/Treg ratio differentiates AU-007 from other IL-2 therapeutic programs. Today’s data support further evaluation of AU-007 and low-dose, subcutaneous aldesleukin as a second-line treatment for melanoma, where limited treatment options exist. Our new Phase 2 cohort augmenting this regimen with anti-PD-1 nivolumab is now enrolling patients and we look forward to presenting preliminary data later this year.” Key findings from interim results of the Phase 1/2 dose escalation and cohort expansion study of AU-007, with data available on 95 patients as of the data cutoff date of March 20, 2025, are as follows: Continued tolerable and manageable safety profile was observed with AU-007 as a monotherapy and in combination with low-dose, subcutaneous aldesleukin at all doses evaluated in Phase 1 dose escalation. No dose-limiting toxicity occurred throughout Phase 1 dose escalation. Most drug-related adverse events were mild and transient Grade 1 or 2 events. The most common treatment-related adverse events in patients who received AU-007 and low-dose, subcutaneous aldesleukin were Grade 1 or 2 fatigue (21%), pyrexia (21%), chills (19%) and infusion-related reaction (15%). The incidence of Grade 3 or 4 treatment-related adverse events in patients who received AU-007 and low-dose, subcutaneous aldesleukin was cytokine release syndrome (1%), lymphopenia (8%) and anemia (3%). All events were transient and resolved, and there were no Grade 5 treatment-related adverse events. Durable objective responses were observed in patients with multiple tumor types enrolled in the Phase 1 dose escalation and Phase 2 cohorts. One patient with metastatic bladder cancer that progressed on an anti-PD-L1 treatment was treated with AU-007 every two weeks (Q2W) and one loading dose of low-dose, subcutaneous aldesleukin, has an ongoing metabolic complete response and continues on treatment for two years. One patient with metastatic nasopharyngeal head and neck cancer that progressed on five prior systemic therapies received AU-007 and low-dose, subcutaneous aldesleukin Q2W. This patient experienced an unconfirmed complete response after 20 months and continues on treatment. Three patients with melanoma refractory to either prior anti-CTLA-4 and anti-PD-1 or anti-PD-1 and anti-LAG-3 therapy were treated with AU-007 Q2W and one loading dose of low-dose, subcutaneous aldesleukin, and experienced deep and durable tumor shrinkages of 100% (complete response in all target lesions, continues on study for 13+ months), 58% (continues on study for 10+ months) and 48% (on study for 13 months). One patient in dose escalation with acral melanoma that progressed rapidly on prior anti-PD-1 therapy received AU-007 and one loading dose of low-dose, subcutaneous aldesleukin. This patient remained on AU-007 therapy for 11 months with disease control. The regimen of AU-007 and low-dose, subcutaneous aldesleukin exhibits distinct pharmacodynamic effects in the class and continues to drive durable decreases in Tregs, increases in CD8 T cells, and corresponding increases in CD8/Treg ratios. A decrease in Tregs appears to be a critical determinant of observed efficacy, with Tregs decreasing in the periphery in the presence of AU-007 at all dose levels. This finding supports AU-007’s overall mechanism of action to control and redirect endogenously produced IL-2 and exogenously administered IL-2 to reduce the Treg population and increase circulating CD8 effector T cell populations. Treg cells are highly immunosuppressive cells that can blunt the immune response to tumors and reduce the durability of responses and progression-free survival. The Phase 2 expansion cohorts evaluating AU-007 and a single loading dose of low-dose, subcutaneous aldesleukin continue to enroll patients with advanced cutaneous melanoma who have failed prior checkpoint inhibitor therapy as well as patients with PD-L1+ non-small cell lung cancer (NSCLC) who have failed prior checkpoint inhibitor therapy. An additional Phase 2 cohort is evaluating AU-007 and low-dose, subcutaneous aldesleukin combined with avelumab (checkpoint inhibitor with ADCC effector function; anti-PD-L1) in PD-L1+ NSCLC in patients who have failed prior checkpoint inhibitor therapy. As announced earlier this month, a new Phase 2 cohort evaluating AU-007 and a single subcutaneous loading dose of low-dose aldesleukin combined with nivolumab (checkpoint inhibitor; anti-PD-1) as a second-line treatment for cutaneous melanoma is enrolling patients who have not received a prior BRAF/MEK inhibitor. Aulos anticipates presenting preliminary clinical data from these two Phase 2 expansion cohorts in the second half of 2025. The poster, “AU-007, a human monoclonal antibody (mAb) that binds to IL-2 and inhibits CD25 binding, plus low-dose aldesleukin, in advanced solid tumors: Phase 2 update,” (Abstract CT178) is accessible to meeting registrants as an electronic poster on the AACR 2025 virtual meeting platform. It is also available on the Aulos Bioscience website in the Abstracts and Publications section. To learn more about the AU-007 clinical trial program, please visit ClinicalTrials.gov (identifier: NCT05267626). For patients and providers in the U.S., please visit www.solidtumorstudy.com. For patients and health professionals in Australia, please visit www.solidtumourstudy.com. About AU-007 AU-007 is a human IgG1 monoclonal antibody designed by leveraging artificial intelligence that is highly selective to the CD25-binding portion of IL-2. With a mechanism of action unlike any other IL-2 therapeutic in development, AU-007 redirects IL-2 to reinforce anti-tumor immune effects. This is achieved by preventing IL-2, either exogenous or secreted by effector T cells, from binding to trimeric receptors on regulatory T cells while still allowing IL-2 to bind and expand effector T cells and NK cells. This prevents the negative feedback loop caused by other IL-2-based treatments and biases the immune system toward activation over suppression. AU-007 also prevents IL-2 from binding to CD25-containing receptors on eosinophils, as well as vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy. About Aulos Aulos Bioscience is an immuno-oncology company working to revolutionize cancer patient care through immune-activating antibody therapeutics that direct patients’ immune systems toward killing tumor cells. Matching world-class machine learning from co-founder Biolojic Design with an in-depth understanding of the immune system, Aulos’ initial clinical candidate, AU-007, is a human antibody designed by leveraging artificial intelligence that harnesses the power of IL-2 to induce tumor killing while limiting the immunosuppression and toxicities typically associated with this validated pathway. The company was founded by Biolojic Design and Apple Tree Partners (ATP) and is led by pioneers in the fields of artificial intelligence, antibody development and cancer immunotherapies. For more information, visit www.aulosbio.com, X (@AulosBioscience) and LinkedIn.

临床结果临床2期免疫疗法AACR会议临床1期

2025-04-16

·靶点圈

靶点解析：IL-2/IL-2R的作用机制与临床数据的大盘点

Vol.01-IL-2/IL-2R靶点概述-IL-2的生物学特性①结构特征：IL-2是由153-169个氨基酸组成的单链多肽，属于γ链细胞因子家族（γc家族），含有四个α-螺旋区域和两个折叠域，分子量为15-16kDa，其基因位于人类染色体4q26-q27，由2个内含子和5个外显子组成。②产生来源：IL-2主要由激活的CD4+T细胞分泌，可通过自分泌和旁分泌发挥作用。此外，激活的CD8+T细胞、NK细胞、自然杀伤T细胞和树突状细胞等也能少量分泌。其产生受T细胞受体（TCR）信号和共刺激信号调控，具有重要的免疫调节功能，对免疫系统的平衡至关重要。在免疫激活时迅速且短暂表达，可促进活化T细胞的克隆扩增，增强CD8+T细胞和NK细胞的细胞毒性。图1 IL-2和IL-2R基因在染色体上的定位以及蛋白质形成和组装过程IL-2R的生物学特性①结构特征：IL-2R是膜结合受体，由IL-2Rα（CD25）、IL-2Rβ（CD122）和IL-2Rγ（CD132）亚基通过非共价键组合而成，各亚基基因也有特定染色体定位，不同亚基组合形成不同亲和力的受体，三条链共同组装形成的高亲和力受体对IL-2的结合力更强，在免疫细胞的激活和功能调节中发挥关键作用。②表达调控：IL-2R的表达和功能受NFAT、AP-1等转录因子及SOCS1、FoxP3等调节剂的调控。此外，可溶性IL-2R（sIL-2R）和IL-2Rα可作为癌症诊断、预后和监测治疗效果的生物标志物，且具有潜在的治疗价值。图2 IL-2R的不同亚基以及它们的位置和意义IL-2/IL-2R系统IL-2通过与IL-2R结合激活淋巴细胞，发挥调节免疫的作用。与受体结合后，激活JAK-STAT、MAPK和PI3K-AKT等信号通路，影响Tregs、CD4⁺T细胞、CD8⁺T细胞和NK细胞等多种免疫细胞的功能。IL-2/IL-2R系统不仅存在于免疫细胞，还广泛分布于中枢神经系统的多种神经细胞中。它们在中枢神经系统中参与神经细胞的生长、存活、神经递质释放以及神经电活动的调节。图3 IL-2相关信号通路表1 参与调节IL-2/IL-2R的转录因子和调节因子IL-2/IL-2R的氨基酸序列IL-2：MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLTIL-2α：MDSYLLMWGLLTFIMVPGCQAELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQVAVAGCVFLLISVLLLSGLTWQRRQRKSRRTIExtracellularHelicalCytoplasmic22-240241-259260-272IL-2β：MLRLYVLVMGVSAFTLQPAAHTGAARSCRFRGRHYKREFRLEGEPVALRCPQVPYWLWASVSPRINLTWHKNDSARTVPGEEETRMWAQDGALWLLPALQEDSGTYVCTTRNASYCDKMSIELRVFENTDAFLPFISYPQILTLSTSGVLVCPDLSEFTRDKTDVKIQWYKDSLLLDKDNEKFLSVRGTTHLLVHDVALEDAGYYRCVLTFAHEGQQYNITRSIELRIKKKKEETIPVIISPLKTISASLGSRLTIPCKVFLGTGTPLTTMLWWTANDTHIESAYPGGRVTEGPRQEYSENNENYIEVPLIFDPVTREDLHMDFKCVVHNTLSFQTLRTTVKEASSTFSWGIVLAPLSLAFLVLGGIWMHRRCKHRTGKADGLTVLWPHHQDFQSYPKExtracellularHelicalCytoplasmic14-343344-369370-398IL-2γ：MLKPSLPFTSLLFLQLPLLGVGLNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRQATQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETExtracellularHelicalCytoplasmic23-262263-283284-369Vol.02-IL-2/IL-2R的生理功能及作用-IL-2/IL-2R在免疫细胞中的作用IL-2对调节性T细胞（Tregs）的胸腺发育、外周诱导、谱系稳定和稳态维持至关重要。IL-2或其受体亚基缺陷会导致Treg功能缺失，引发自身免疫疾病。此外，IL-2对CD8+T细胞和CD4+T细胞的分化和功能也有重要影响，对维持免疫平衡具有重要意义。图4 IL-2和IL-2R的生物学功能IL-2/IL-2R在肿瘤微环境中的作用在肿瘤微环境（TME）中，IL-2/IL-2R信号通路作用复杂，既可促进Tregs扩增抑制抗肿瘤免疫，也能促进细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞浸润增强抗肿瘤免疫。可通过调节效应T细胞和Tregs的平衡影响肿瘤生长，还与肿瘤的预后相关，失调时可能预示不良预后。此外，IL-2/IL-2R对NK细胞、巨噬细胞、中性粒细胞、B细胞、DCs和MDSCs等免疫细胞在TME中的功能均有调节作用，影响肿瘤的发生、发展和免疫逃逸。图5 IL-2/IL-2R在肿瘤微环境中的作用IL-2/IL-2R在免疫调节中的双重作用①免疫激活：IL-2作为T细胞的关键生长因子，在免疫反应启动时，促进效应T细胞的增殖和激活，增强机体对病原体的免疫防御。②免疫耐受：Tregs组成性表达高水平的IL-2Rα，能有效竞争摄取IL-2，限制效应T细胞的激活，维持免疫稳态，防止自身免疫疾病的发生。图6 由不同IL-2R组成介导的IL-2信号传导的双重作用高剂量与低剂量IL-2疗法①高剂量IL-2（HDIL-2）用于治疗转移性癌症，虽有一定疗效，但会引发严重副作用，如毛细血管渗漏综合征、低血压等，还会导致Tregs扩增和维持、血小板减少等系统异常。②低剂量IL-2（LDIL-2）疗法利用Treg对IL-2的高敏感性，选择性扩增Treg，在动物研究和临床试验中显示出良好的耐受性和一定的治疗效果，但也存在一些剂量相关的轻度至中度不良反应。图7 高剂量与低剂量IL-2疗法的对比IL-2/IL-2R在疾病中的作用①癌症免疫治疗：高剂量IL-2疗法在20世纪90年代被FDA批准用于治疗转移性黑色素瘤和转移性肾细胞癌，能够促进多种免疫细胞的生长、分化和功能发挥，增强机体的抗肿瘤免疫反应，部分患者可实现持久缓解甚至完全缓解。但高剂量IL-2疗法会引发严重副作用，限制了其广泛应用。尽管降低剂量可减少毒性，但疗效也会降低。②自身免疫性疾病治疗：低剂量IL-2疗法旨在通过选择性靶向Treg细胞上的高亲和力IL-2R，调节免疫系统，治疗自身免疫性疾病。可增加Treg细胞数量，调节免疫平衡，用于治疗如1型糖尿病、类风湿关节炎、系统性红斑狼疮和多发性硬化症等自身免疫性疾病。但其长期安全性和有效性仍需进一步研究，存在局限性，如部分患者临床症状改善不彻底、停药后疗效不佳等。③移植领域应用：在器官移植中，IL-2可促进Tregs存活，限制效应T细胞激活，诱导免疫耐受，减少移植排斥反应。低剂量IL-2疗法在动物实验和临床研究中显示出促进移植物长期存活的潜力，但仍面临选择性激活Tregs而避免激活效应T细胞的挑战。Vol.03-IL-2/IL-2R的临床应用-IL-2/IL-2R的临床药物清单表2 IL-2的临床药物表3 IL-2R的临床药物第二代IL-2疗法①分子修饰：通过PEGylation、突变、融合蛋白和糖基化等方法对recIL-2进行修饰，旨在增强其疗效、降低毒性、提高选择性。②递送系统改进：采用纳米颗粒和溶瘤腺病毒等方式改进recIL-2的递送，可实现靶向给药和控制药物释放。图8 基于IL-2的免疫疗法的新方法聚乙二醇化IL-2：通过聚乙二醇（PEG）修饰IL-2，改善其溶解度和药代动力学。如NKTR-214，是最早的PEGylated IL-2R激动剂之一，为IL-2Rβ偏向性激动剂，可优先扩增CD8+Teff和NK细胞，减少与高亲和力受体结合，降低Tregs扩增，延长半衰期，减少给药频率和毒性。此外，还有THOR-707、NL-201、STK-012和TransConIL-2β/γ等也在研发中，各有其作用特点和临床研究进展。IL-2融合蛋白：与蛋白融合可延长IL-2的半衰期（如MDNA11），可选择性激活NK和幼稚CD8⁺T细胞，在临床前模型中展现出强大的抗肿瘤功效；以及IL-2/IL-2Rα融合蛋白（如ALKS4230），能选择性刺激IL-2Rβγc，在多种癌症治疗的临床试验中进行评估。双特异性免疫分子：如GI-101、eciskafusp-alfa、simlukafusp-alfa和IBI363等，具有两个结合域，能同时靶向不同表位或抗原，分别通过不同机制发挥作用，增强药物向肿瘤的递送并产生协同效应。IL-2/mAb复合物：如ANV419、SLC-3010、AU-007、Darleukin和Daromun等，将IL-2与单克隆抗体结合，通过阻断IL-2与IL-2Rα的结合，优先激活CD8⁺T和NK细胞，部分药物已进入临床试验阶段。脂质纳米颗粒（LNP）封装的编码IL-2的mRNA：如BNT151和BNT153，利用LNP包裹编码IL-2的mRNA，进入细胞后产生IL-2，增强抗肿瘤免疫力，相关临床试验正在进行或已完成但结果未报道。溶瘤病毒：如TILT-123，是一种编码IL-2和TNF-α的溶瘤腺病毒，可破坏癌细胞，增强T细胞浸润和细胞毒性，初步显示出良好的耐受性和一定的临床反应。联合治疗方法：与免疫检查点抑制剂联合、与放疗联合、与过继细胞疗法联合以及使用正交IL-2/IL-2Rb突变对，这些联合疗法在临床前和临床试验中显示出增强抗肿瘤效果的潜力。Vol.04-IL-2/IL-2R在不同疾病的应用-慢性感染在慢性感染中，IL-2可激活耗竭的CD8+T细胞，增强其增殖能力、细胞毒性和细胞因子分泌能力，使其重新发挥抗病毒作用。IL-2还能促进记忆性CD8+T细胞的产生和维持，有助于长期控制感染。目前针对慢性感染的IL-2免疫疗法大多还处于临床前研究或早期临床试验阶段，尚未广泛应用于临床治疗。中枢神经系统疾病多发性硬化症（MS）：IL-2/IL-2R基因多态性影响MS易感性，患者血清中IL-2和sIL-2R水平升高与疾病进展相关，脑脊液IL-2水平与残疾程度、疾病活动度及风险标志物相关。在实验性自身免疫性脑脊髓炎（EAE）模型中，也有类似发现。IL-2/IL-2R的相关治疗可通过调节NK细胞和Tregs功能来减轻炎症。阿尔茨海默病（AD）：IL-2在AD患者中的表达模式复杂，血浆IL-2水平在疾病不同阶段有变化，与认知功能和病理改变有关。在APP/PS1小鼠等模型及临床研究中，发现IL-2在脑内的表达变化及对疾病的潜在影响。低剂量IL-2治疗可调节Tregs数量，改善认知功能。缺血性中风（IS）：IS发病后，患者血清和脑内IL-2及IL-2R表达发生变化，且与预后相关，血清IL-2水平在急性期降低，之后升高，而sIL-2Rα水平与病情严重程度相关，但不同年龄段的表达变化存在差异。可通过调节IL-2/IL-2R，作用于Tregs和CD8+T细胞，可改善预后，减少脑损伤。脑炎：在不同类型脑炎中，IL-2表达不同。如抗NMDAR脑炎患者血清IL-2水平升高，HSV-1诱导的脑炎小鼠脑内IL-2等细胞因子表达上调，SSPE患者血清IL-2水平也显著升高，但IL-2与脑炎预后的关系尚不清楚。部分自身免疫性脑炎患者接受低剂量IL-2治疗有效，在感染性脑炎中，IL-2可增强免疫反应，降低死亡率。图9 IL-2在中枢神经系统疾病中的作用自身免疫性和风湿性疾病血管炎：低剂量IL-2可治疗丙型肝炎病毒（HCV）诱导的血管炎患者，能改善患者症状，扩大Treg细胞数量，减轻炎症和氧化应激。1型糖尿病（T1D）：多项临床试验表明，低剂量IL-2疗法在T1D患者中耐受性良好，能有效扩增Treg群体，部分研究还观察到对胰岛β细胞功能的改善，且未发现对糖尿病控制、胰岛素需求或β细胞功能的负面影响。联合治疗虽显示出潜力，但存在脱靶效应。系统性红斑狼疮（SLE）：低剂量IL-2疗法可减少SLE患者的TFH和TH17细胞的频率，增加TFR细胞的频率，促进Treg细胞的扩增，改善疾病严重程度，降低感染风险，部分患者疾病活动度降低，且安全性良好，不同研究在剂量、治疗方案和持续时间上有所差异。干燥综合征：低剂量IL-2可逆转原发性干燥综合征患者外周血中TH17细胞和Treg细胞的失衡状态，但还需体内实验进一步验证。类风湿关节炎：低剂量IL-2治疗可能恢复循环中的Treg细胞，减轻疾病活动度。皮肌炎和特发性炎症性肌病：低剂量IL-2治疗可增加Treg细胞数量，改善患者临床症状和缓解情况。自身免疫性肝炎：在自身免疫性肝炎小鼠模型中，低剂量IL-2治疗可增加循环和肝脏内的Treg细胞，改善肝脏特异性ALT水平。在临床病例中，该疗法安全有效，能限制肝脏损伤，其益处可能主要源于Treg细胞的增加。其他疾病：在缺血性心脏病、溃疡性结肠炎等炎症性疾病的临床试验中显示出一定潜力，还在蛛网膜下腔出血损伤、严重斑秃和骨髓增生异常综合征等疾病的治疗中进行探索。但在肌萎缩侧索硬化症（ALS）的试验中未显示出临床疗效，可能与治疗持续时间较短有关。表4 IL-2治疗自身免疫性疾病和风湿性疾病的临床试验移植慢性移植物抗宿主病（GVHD）：低剂量IL-2治疗可有效诱导Treg介导的免疫耐受，促进其存活、增殖和胸腺输出，对常规T细胞影响较小，使部分患者临床症状改善，恢复Treg细胞的稳态。造血干细胞移植（HSCT）：在HSCT患者中，低剂量IL-2治疗可诱导Treg和NK细胞增加，在预防GVHD和促进移植物抗白血病效应方面有一定效果，部分患者症状改善且能减少糖皮质激素用量。然而，该疗法也存在感染并发症、影响抗体反应等问题，其长期效果和风险仍需进一步研究。实体器官移植（SOT）：动物实验表明，低剂量IL-2在不同SOT模型中效果各异。在一些模型中，它可增加Treg数量、延长移植物存活时间；但在非人类灵长类动物的肾脏移植模型中，却会引发排斥反应，提示在SOT中使用低剂量IL-2需谨慎。目前关于低剂量IL-2在SOT中的临床研究较少，已有的一项肝移植临床试验因安全问题提前终止。总结与展望RenyuBioIL-2治疗面临的主要挑战是在免疫刺激和免疫抑制之间难以平衡。高剂量用于癌症治疗时毒性大，低剂量用于自身免疫性疾病治疗时效果有限且可能存在安全隐患。未来需要关注降低毒性、激活肿瘤特异性记忆T细胞反应，并根据患者的免疫状态和肿瘤特征进行个性化治疗，进一步优化IL-2的使用策略，如精准的剂量调控、开发更有效的IL-2变体，以及探索联合治疗方案，以充分发挥其治疗潜力，满足不同疾病的治疗需求。抗体发现服务 & 产品01羊驼免疫&骆驼免疫—自建现代化养殖农场02万亿级天然抗体库产品—轻松DIY科研抗体03配套产品—助您轻松搭建基因工程抗体平台关于仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！protocol 获取 / 产品咨询邮箱｜find@renyubio.com电话｜19136178673地址｜成都市经开区科技产业孵化园关注我们，持续更新中参考文献Tanigawa K, Redmond WL. Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy. Oncoimmunology. 2025 Dec;14(1):2452654.Paul P, Choong C, Heinemann J, Al-Hallaf R, Agha Z, Ganatra S, Abdulrahman L, Sinha A, Kumar H, Nourbakhsh B, Hamad ARA. The Lasting Impact of IL-2: Approaching 50 Years of Advancing Immune Tolerance, Cancer Immunotherapies, and Autoimmune Diseases. Immunol Invest. 2025 Mar 17:1-15.Zhang Y, Kong Q, Fan J, Zhao H. Interleukin-2 and its receptors: Implications and therapeutic prospects in immune-mediated disorders of central nervous system. Pharmacol Res. 2025 Mar;213:107658.Roser LA, Sommer C, Ortega Iannazzo S, Sakellariou C, Waibler Z, Gogesch P. Revival of recombinant IL-2 therapy - approaches from the past until today. J Immunotoxicol. 2024 Oct;21(sup1):S38-S47. Im SJ, Lee K, Ha SJ. Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends. Exp Mol Med. 2024 Sep;56(9):1900-1908.Shouse AN, LaPorte KM, Malek TR. Interleukin-2 signaling in the regulation of T cell biology in autoimmunity and cancer. Immunity. 2024 Mar 12;57(3):414-428. Rokade S, Damani AM, Oft M, Emmerich J. IL-2 based cancer immunotherapies: an evolving paradigm. Front Immunol. 2024 Jul 24;15:1433989. Sprent J, Boyman O. Optimising IL-2 for Cancer Immunotherapy. Immune Netw. 2024 Jan 26;24(1):e5.Zhang R, Zhao Y, Chen X, Zhuang Z, Li X, Shen E. Low-dose IL-2 therapy in autoimmune diseases: An update review. Int Rev Immunol. 2024 May;43(3):113-137. Lykhopiy V, Malviya V, Humblet-Baron S, Schlenner SM. "IL-2 immunotherapy for targeting regulatory T cells in autoimmunity". Genes Immun. 2023 Oct;24(5):248-262.Muhammad S, Fan T, Hai Y, Gao Y, He J. Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies. Mol Cancer. 2023 Jul 29;22(1):121. Hernandez R, Põder J, LaPorte KM, Malek TR. Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat Rev Immunol. 2022 Oct;22(10):614-628.Zhou P. Emerging mechanisms and applications of low-dose IL-2 therapy in autoimmunity. Cytokine Growth Factor Rev. 2022 Oct;67:80-88.Graßhoff H, Comdühr S, Monne LR, Müller A, Lamprecht P, Riemekasten G, Humrich JY. Low-Dose IL-2 Therapy in Autoimmune and Rheumatic Diseases. Front Immunol. 2021 Apr 1;12:648408.

细胞疗法临床结果临床研究免疫疗法

2025-04-15

·PipelineReview

Aulos Bioscience Doses First Patient in Phase 2 Cohort Evaluating AU-007 in Combination With Nivolumab for Second-Line Treatment of Melanoma

LARKSPUR, CA, USA I April 14, 2025 I Aulos™ Bioscience, an immuno-oncology company working to revolutionize cancer care through development of immune-activating antibody therapeutics, today announced dosing of its first patient with a combination of AU-007, the anti-PD-1 antibody nivolumab and low-dose, subcutaneous aldesleukin in a Phase 2 expansion cohort focused on second-line treatment of melanoma. This new cohort is part of Aulos’ Phase 1/2 clinical trial of AU-007 in patients with unresectable locally advanced or metastatic cancer. Preliminary Phase 2 data presented in November at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting showed that a combination of AU-007 and low-dose, subcutaneous aldesleukin is clinically active in patients with melanoma, with durable objective responses achieved. The additional Phase 2 cohort in melanoma now allows the nivolumab combination portion of this study to progress. “We are excited that the first patient is receiving treatment in this new Phase 2 cohort evaluating AU-007 in combination with nivolumab,” said Aron Knickerbocker, Aulos Bioscience’s president and chief executive officer . “Given its unique mechanism of action and the positive data presented to date on AU-007 and low-dose, subcutaneous aldesleukin, we believe that AU-007 holds real promise as a novel immuno-oncology treatment in combination with checkpoint inhibitors in multiple cancer types. These include non-small cell lung cancer, for which we initiated a Phase 2 cohort with the anti-PD-L1 antibody avelumab in November, and now melanoma.” AU-007 is the first human monoclonal antibody designed with the assistance of artificial intelligence to enter a human clinical trial. The antibody harnesses the power of interleukin-2 (IL-2) by binding precisely to the portion of IL-2 that binds to CD25, which prevents IL-2 from binding to high-affinity IL-2 receptors on Tregs, vasculature, pulmonary tissue and eosinophils. This redirects IL-2 to medium-affinity receptors on effector T cells (Teffs) and natural killer (NK) cells, which expand and kill tumor cells. Aulos anticipates presenting preliminary data from the Phase 2 cohort evaluating AU-007, nivolumab and low-dose, subcutaneous aldesleukin as a second-line treatment for melanoma in the second half of 2025. The company will present new Phase 2 data for AU-007 and low-dose, subcutaneous aldesleukin without a checkpoint inhibitor as a second-line treatment for melanoma at the American Association for Cancer Research (AACR) Annual Meeting later this month. To learn more about the AU-007 clinical trial program, please visit ClinicalTrials.gov (identifier: NCT05267626 ). For patients and providers in the U.S., please visit www.solidtumorstudy.com . For patients and health professionals in Australia, please visit www.solidtumourstudy.com . About AU-007 AU-007 is a human IgG1 monoclonal antibody designed by leveraging artificial intelligence that is highly selective to the CD25-binding portion of IL-2. With a mechanism of action unlike any other IL-2 therapeutic in development, AU-007 redirects IL-2 to reinforce anti-tumor immune effects. This is achieved by preventing IL-2, either exogenous or secreted by effector T cells, from binding to trimeric receptors on regulatory T cells while still allowing IL-2 to bind and expand effector T cells and NK cells. This prevents the negative feedback loop caused by other IL-2-based treatments and biases the immune system toward activation over suppression. AU-007 also prevents IL-2 from binding to CD25-containing receptors on eosinophils, as well as vasculature and pulmonary endothelium, which may significantly reduce the vascular leak syndrome and pulmonary edema associated with high-dose IL-2 therapy. About Aulos Aulos Bioscience is an immuno-oncology company working to revolutionize cancer patient care through immune-activating antibody therapeutics that direct patients’ immune systems toward killing tumor cells. Matching world-class machine learning from co-founder Biolojic Design with an in-depth understanding of the immune system, Aulos’ initial clinical candidate, AU-007, is a human antibody designed by leveraging artificial intelligence that harnesses the power of IL-2 to induce tumor killing while limiting the immunosuppression and toxicities typically associated with this validated pathway. The company was founded by Biolojic Design and Apple Tree Partners ( ATP ) and is led by pioneers in the fields of artificial intelligence, antibody development and cancer immunotherapies. For more information, visit www.aulos.com , X ( @AulosBioscience ) and LinkedIn . SOURCE: Aulos Bioscience

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适应症	最高研发状态	国家/地区	公司	日期
实体瘤	临床2期	美国	Aulos Bioscience, Inc.	2024-01-25
晚期恶性实体瘤	临床2期	美国	Aulos Bioscience, Inc.	2022-04-04
晚期恶性实体瘤	临床2期	澳大利亚	Aulos Bioscience, Inc.	2022-04-04
局部晚期不可切除癌	临床2期	美国	Aulos Bioscience, Inc.	2022-04-04
局部晚期不可切除癌	临床2期	澳大利亚	Aulos Bioscience, Inc.	2022-04-04
皮肤黑色素瘤	临床2期	美国	Aulos Bioscience, Inc.	2022-04-04
皮肤黑色素瘤	临床2期	澳大利亚	Aulos Bioscience, Inc.	2022-04-04
肿瘤转移	临床2期	美国	Aulos Bioscience, Inc.	2022-04-04
肿瘤转移	临床2期	澳大利亚	Aulos Bioscience, Inc.	2022-04-04
非小细胞肺癌	临床2期	美国	Aulos Bioscience, Inc.	2022-04-04

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适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


AU-007 (AACR2025)	临床2期	晚期恶性实体瘤	86	AU-007	襯鏇鹹構積壓鑰夢淵顧(製網壓構繭壓選艱壓蓋) = no Grade 5 TRAE occurred 獵憲繭範遞齋顧壓廠鑰 (選築衊製獵餘鹹窪構憲 )	积极	2025-04-29
NCT05267626 (SITC2024) 人工标引	临床1/2期	晚期恶性实体瘤	-	AU-007	憲齋衊糧壓觸淵觸餘鑰(廠願顧鹹製獵壓鑰繭鏇) = None 積顧簾繭鹹淵艱憲衊膚 (製淵構艱膚鏇齋顧選夢 ) 更多	积极	2024-11-05
				AU-007 + aldesleukin
NCT05267626 (ASCO2024) 人工标引	临床1/2期	晚期恶性实体瘤	53	AU-007	糧鏇齋網鹹積憲鬱獵鏇(積襯鑰鬱鹽窪鹽觸夢衊) = 繭繭觸積衊餘網選窪選範壓憲糧夢艱夢餘鹹襯 (衊鹽觸鬱願窪遞艱鏇襯 )	积极	2024-05-24
				AU-007AU-007 Q2W + one aldesleukin (Arm 1B)	糧鏇齋網鹹積憲鬱獵鏇(積襯鑰鬱鹽窪鹽觸夢衊) = 夢願構網積繭鏇齋壓繭範壓憲糧夢艱夢餘鹹襯 (衊鹽觸鬱願窪遞艱鏇襯 ) 更多
NCT05267626 (Phase 1 study, SITC2023)	临床1期	晚期恶性实体瘤	24	AU-007	簾鏇淵鑰遞鹽衊積憲網(簾簾獵艱網範糧襯願簾) = no DLTs 簾鹹願糧鑰憲積積鬱糧 (觸構夢簾夢鹹顧鏇壓積 ) 更多	积极	2023-11-02
				AU-007 + aldesleukin
NCT05267626 (ASCO 12023 \| ASCO 22023) 人工标引	临床1/2期	HR阳性/HER2低表达实体瘤	4	AU-007	膚獵醖構選繭選壓膚簾(齋網鬱糧壓膚選醖範蓋) = 製獵夢觸網壓壓鏇鹽觸積醖壓顧築糧淵膚構醖 (壓糧製壓觸廠築築簾獵 )	积极	2023-05-26