Phase II Randomized Study Evaluating a Pragmatic Approach to Adoptive Cell Therapy (ACT) Using an IL2 Analog (ANV419) vs High Dose IL2 After Tumor Infiltrating Lymphocytes (TIL) Therapy in Patients With Melanoma, NSCLC and Cervical Cancer

Background:
The presence of T-lymphocytes in resected tumor samples derived from long-term survival patients and the fact that reinvigoration of their functionality through the administration of specific immune-therapies can lead to remarkable antitumor responses supports that lymphocytes play a critical role in cancer immunity.
TIL-based ACT (Adoptive cell therapy using tumor-infiltrating lymphocytes product) is a modality of ACT used to treat patients with multiple types of cancer and it consists in the adoptive transfer of ex vivo expanded autologous tumor-infiltrating lymphocytes obtained from tumor resection or tumor biopsies in patients following a non-myeloablative lymphodepleting (NMA-LD) chemotherapy. Ex vivo expansion of TIL relies on the non-specific expansion of lymphocytes present in tumor single cell suspensions or tumor fragments in high dose IL-2.
Although proven efficacy in selected, the HD-IL-2 use remains relatively restricted due to toxicity. Due to the short serum half-life and the need to achieve an immune-modulatory effect in the tissues, IL-2 must be given in doses that induce severe systemic toxicities, including capillary leak syndrome (CLS), pulmonary edema, hypotension, acute renal insufficiency, and rarely myocarditis, limiting its applicability in cancer. Studies comparing HD-IL-2 with lower doses both in renal cell carcinoma and metastatic melanoma to minimize toxicity demonstrated the superiority of the high dose regimens in both diseases. These drawbacks of HD-IL-2 use encouraged the development of improved IL-2-based biologic agents with higher selectivity for effector immune cell subsets, reduced toxicity, and prolonged half-life.
ANV419 is a novel IL-2 agent, which has been developed as a preferentially IL-2Rβγ directed fusion protein with a longer half-life. It has shown high effector selectivity and a favorable safety profile in preclinical testing, including in nonhuman primates, and it has been investigated in an ongoing open-label, dose-escalation Phase I Study in multiple tumor types. he safety profile of ANV419 is characterized by pyrexia, nausea, vomiting, ALT/AST changes and CRS in some patients. Most events are low grade and self-limiting and manageable with standard supportive care. ANV419 was well-tolerated by most patients. No patient discontinued treatment due to treatment related AE.
Taking all the previous information into account, the primary objectives of this study are:
1. To determine whether TIL-ACT using the IL-2 analog ANV419 reduces the mean number of predefined grade ≥3 relevant adverse events related to interleukin use (based on Common Terminology Criteria for Adverse Events v5.0 - CTCAE v5.0) compared to TIL-ACT using HD-IL-2.
2. To determine whether TIL-ACT using the IL-2 analog improves patient´s reported outcomes (PRO) compared to TIL-ACT using HD-IL-2

开始日期2025-01-15

申办/合作机构

Vall d'Hebron Institut d'Oncologia

[+1]

NCT05641324

/ Terminated临床1期

A Phase 1 Study of ANV419 as Monotherapy, and ANV419 in Combination With Daratumumab or With Lenalidomide Plus Low-Dose Dexamethasone, in Patients With Relapsed or Refractory Multiple Myeloma (OMNIA-2)

The purpose of this study is to evaluate the safety and tolerability of ANV419 monotherapy followed by ANV419 in combination with lenalidomide plus low-dose dexamethasone or ANV419 in combination with daratumumab.

开始日期2023-02-10

申办/合作机构

Anaveon AG

NCT05578872

/ Completed临床1/2期

A Phase 1/2 Study of ANV419 as Monotherapy or in Combination With Anti-PD-1 or Anti-CTLA-4 Antibody Following Anti-PD-1/Anti-PD-L1 Antibody Treatment in Patients With Unresectable or Metastatic Cutaneous Melanoma (OMNIA-1)

The purpose of this study is to evaluate the efficacy and safety of ANV419 monotherapy or the combination of ANV419 with anti-PD1 antibody or with anti-CTLA4 antibody in adult participants with advanced (unresectable or metastatic) cutaneous melanoma. The study has 3 parts. Part 1 to evaluate ANV419 in monotherapy and Parts 2 and 3 to evaluate ANV419 in combination with anti-PD1 antibody or anti-CTLA4 antibody. Parts 2 and 3 were not initiated, as the prespecified efficacy criteria to graduate to Part 2 were not met at the interim analysis of Part 1.

开始日期2022-12-16

申办/合作机构

Anaveon AG

100 项与 ANV-419 相关的临床结果

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100 项与 ANV-419 相关的转化医学

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100 项与 ANV-419 相关的专利（医药）

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项与 ANV-419 相关的文献（医药）

2024-12-31·mAbs

Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy

Article

作者: Regnier, Catherine ; Rondeau, Jean-Michel ; Popp, Simone ; Katopodis, Andreas ; Egli, Nicole ; Huber, Christoph ; Richter, Kirsten ; Murer, Patrizia ; Petersen, Laetitia ; Brannetti, Barbara

Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor βγ (IL-2 Rβγ) activation by sterically hindering IL-2 from binding to IL-2 Rα. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Rα. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8⁺ T cells and natural killer (NK) cells over T_regs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2⁺ xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin.

2024-05-01·Journal for ImmunoTherapy of Cancer

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors

Article

作者: Stephane Champiat ; Aurelien Marabelle ; Yohann Loriot ; Justin Cagnat ; Julia Delahousse ; Laurent Mathiot ; Francois-Xavier Danlos ; David Combarel ; Santiago Ponce ; Sophie Broutin ; Kaissa Ouali

Patients with advanced cancer, previously treated with immune checkpoint blockade therapy, may retain residual treatment when undergoing the initial infusion of experimental monotherapy in phase 1 clinical trials. ANV419, an antibody-cytokine fusion protein, combines interleukin-2 (IL-2) with an anti-IL-2 monoclonal antibody, aiming to stimulate the expansion of CD8 T and natural killer lymphocytes while restricting regulatory T lymphocytes. In the recent publication of the phase 1 dose escalation study of ANV419, a notable gap exists in detailed information regarding patients’ prior antitumoral treatments, specifically programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) targeted monoclonal antibodies. Some patients likely retained residual anti-PD-1/PD-L1 monoclonal antibodies, potentially influencing the outcomes of ANV419. In a separate clinical cohort, we retrospectively measured the residual concentration of nivolumab and pembrolizumab, revealing persistent serum concentrations of anti-PD-1/PD-L1 antibodies even months after treatment cessation. This underscores the importance of comprehensively documenting prior immunotherapy details in clinical trials. Such information is crucial for understanding potential interactions that may impact both immunological and clinical effects.

2023-11-01·Journal for immunotherapy of cancer

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors

Article

作者: Sanchez Perez, Vicky ; Bucher, Christoph ; Corral de la Fuente, Elena ; Joerger, Markus ; Calvo, Emiliano ; Jethwa, Sangeeta ; Lopez, Juanita ; Alonso, Guzmán ; Garralda, Elena ; Hess, Dagmar ; Laubli, Heinz ; König, David

Background:

ANV419 is a stable antibody–cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor βγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells.

Methods:

ANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24–364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023).

Results:

Forty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR).

Conclusions:

ANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors.

Trial registration number:

NCT04855929.

项与 ANV-419 相关的新闻（医药）

2026-05-28

·BioSpace

Anaveon Reports Clinical Benefit of ANV600 in the EXPAND-1 Phase 1 Clinical Trial at ASCO 2026 and Actively Seeks Partners for its Legacy Oncology Portfolio

BASEL, Switzerland, May 28, 2026 (GLOBE NEWSWIRE) -- Anaveon, a late-stage preclinical biotechnology company focused on reprogramming the immune system for the treatment of autoimmune and inflammatory diseases, today announced that new clinical data from its legacy oncology asset ANV600 (sunekafusp alpha) will be presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. Following its strategic pivot to immunology, Anaveon is actively seeking global development and commercialization partners for its oncology portfolio to maximize the potential of these highly differentiated assets. ANV600 is a first-in-class, non-blocking PD-1-targeted IL-2R-βγ agonist designed to selectively expand tumor-reactive PD-1 + CD8 + effector T cells while reducing the toxicities historically associated with IL-2 therapy. It is compatible with existing Check Point Inhibitors (CPI) and is positioned for use in CPI-resistant and CPI-relapsed patients. Key results from the EXPAND-1 Phase 1 study will be highlighted in the poster: The encouraging preliminary antitumor activity observed with ANV600 should be investigated further through additional clinical studies with larger patient populations, ANV600 is well tolerated as a monotherapy and in combination with pembrolizumab, A complete response (CR) was observed in a patient with NSCLC (non-small cell lung cancer) previously progressing on CPI and treated with ANV600 monotherapy at 120 µg/kg Q2W. Partial responses (PRs) were reported for two patients treated respectively with 30 µg/kg and 60 µg/kg ANV600 Q2W in combination with pembrolizumab Q3W, Patients experienced target lesion shrinkage in 29% of patients receiving ANV600 monotherapy and 24% of patients receiving ANV600 plus pembrolizumab, Disease control defined as Complete Response, Partial Response, or Stable Disease observed in 42% of patients treated with ANV600 monotherapy and 59% of the patients receiving ANV600 and Pembrolizumab, Recommended Phase 2 dose of 90 µg/kg weekly for 4 weeks followed by 150 µg/kg Q2W established, Patients Treatment with ANV600 resulted in higher absolute counts of CD8 + T cells and NK cells over regulatory T cells. “Patients with advanced solid tumors treated with ANV600 derived meaningful clinical benefit, with approximately 24% of patients achieving a Complete Response, Partial Response or durable Stable Disease maintained for at least 18 weeks (≥3 tumor assessments),” said Prof. Dr. med. Markus Jörger of Health Ostschweiz (HOCH) in St. Gallen (Switzerland). “The trial provided a valuable treatment option for patients whose disease had progressed beyond available therapies. ANV600 demonstrated a promising safety-efficacy profile, together with compelling proof-of-mechanism in patients with advanced solid tumors.” ASCO Annual Meeting abstracts may be accessed online via . Presentation Details: Title: Safety, PK/PD, and efficacy results from Expand-1: A phase 1 dose escalation study of the novel PD-1 targeted IL-2R-βγ agonist sunekafusp alpha (ANV600) as a single agent and in combination with pembrolizumab in patients with advanced solid tumors. First Author: Markus Joerger Abstract number: 2587 Session Title: Development Therapeutics- Immunotherapy Poster board: 377 Location, Date and Time: Hall A, May 30, 2026, 1:30 to 4:30 pm, CDT “With established clinical benefits and strong interest from current clinical investigators, we believe that ANV600 is ideally suited for a partner with the resources and expertise to bring it forward in CPI-resistant NSCLC and other immuno-oncology indications,” added Thaminda Ramanayake , Chief Executive Officer of Anaveon . Anaveon’s proprietary oncology product portfolio is built around a non-blocking PD-1 targeted cytokine platform. This highly selective “cis-signaling” proximity-activated delivery of cytokines is precise and combinable with Check Point Inhibitors. In addition to ANV600, the platform includes ANV700, a preclinical proximity-activated PD-1-targeted IL-21 fusion protein with potential for synergistic effects when combined with IL-2-based approaches and another undisclosed preclinical program. Included in the oncology portfolio is ANV419, an earlier generation (non-PD-1-targeted) IL-2/anti-IL-2 fusion protein with demonstrated safety in prior clinical studies. The company is now prioritizing its core immunology pipeline and is open to various partnering structures (license, co-development, or acquisition) for the oncology platform and portfolio. For partnering inquiries, please, contact: collaborations@anaveon.com . Media contact: Benz Advisory Beatrix Benz Email: beatrix.benz@anaveon.com Tel: +41 79 256 77 73 About Anaveon: Anaveon AG is a late-stage preclinical biotechnology company headquartered in Basel, Switzerland. The company is dedicated to transforming lives by precisely modulating the immune system to address high unmet needs in autoimmune diseases and inflammatory disorders. Our therapeutics target central regulatory nodes of the immune system to selectively eliminate or reprogram pathogenic immune cells and restore durable immune balance. Anaveon is backed by Syncona, Forbion, Blue Owl, Novartis Venture Fund, Pfizer Ventures and Pontifax. About ANV600: ANV600 is a novel PD-1–targeted IL-2R-βγ agonist that binds PD-1 on a unique non-blocking epitope, distinct from that targeted by pembrolizumab and other PD-1 checkpoint inhibitors. It is designed to preferentially stimulate PD-1⁺ CD8⁺ T cells with a pre-exhausted, cytotoxic phenotype, aiming to activate tumor antigen-experienced T cells within the tumor microenvironment. This targeted, non-blocking PD-1 approach may reduce IL-2–related toxicities, enhance tumor selectivity, and potentiate responses in checkpoint-refractory tumors without compromising combination therapies. Find out more at > anaveon.com

2026-02-24

·递因递药

【免疫疗法】将IL2打乱重构：一种新型的PD-1靶向IL-2Rβγ激动剂ANV600

白介素-2（IL-2）在抗肿瘤免疫中具有关键作用，但其临床应用受限于系统性毒性及对调节性T细胞（Treg）的非选择性激活。近日，Anaveon公司在《Journal for ImmunoTherapy of Cancer》发表了其首创（First-in-Class）分子ANV600的研究数据。该分子是在ANV419的基础上，通过增加靶向PD-1非阻断位点，使其选择性激活IL-2Rβγ受体，实现了在肿瘤微环境中的精准免疫动员。一、传统IL-2疗法的问题不赘述。非选择性受体激活：传统IL-2优先结合表达IL-2Rα（CD25）的Treg细胞，产生免疫抑制效应，抵消抗肿瘤活性。严重的系统性毒性：药物结合血管内皮细胞引发毛细血管渗漏综合征（VLS），导致临床耐受剂量极低，难以维持有效的治疗窗口。二、 ANV600分子的结构设计与靶向策略 ANV600是一款双特异性抗体-细胞因子融合蛋白，其核心设计是通过蛋白质工程实现“顺式（cis）”激活，即药物分子同时结合同一细胞表面的PD-1和IL-2受体。 1. PD-1靶向性：ANV600的抗PD-1臂以高亲和力结合人PD-1（KD 5.0E-10）。其结合表位与帕博利珠单抗（Pembrolizumab）及纳武利尤单抗（Nivolumab）不产生空间竞争，支持三方同时结合。 2. 受体选择性：ANV600的IL2来自ANV419，利用一种巧妙的打乱重构的设计达到IL2受体选择性。简单说，将IL2 从K96和N97（按照前体序列编码）之间截开，创造一个新的N端和C端，同时将原N端P22和和C端T153连接，形成一个具有相同IL2结构的重组分子。将该重组分子插入至抗IL-2 抗体轻链，使抗IL-2 抗体遮蔽与α受体的结合。 IL-2Rα (CD25)：由于抗IL-2抗体的空间屏蔽效应，ANV600对CD25几乎不表现出任何结合活性。 IL-2Rβ (CD122)：ANV600保留了对CD122的正常结合力，亲和力水平与天然IL-2基本相当（KD 0.322 nM）。 3. 体外激活效能：在PD-1阳性的T细胞中，ANV600诱导STAT5磷酸化的EC50值显著降低。与非靶向的IL-2Rβγ激动剂相比，其激活效能提高了约88倍，验证了PD-1靶向带来的精准激活优势。 ANV600通过PD-1锚定，实现IL-2信号在同一细胞内的“顺式激活（Cis-activation）”，在降低系统暴露量的同时显著提升局部信号强度。三、 ANV600体内药效学评估研究团队在多个同系肿瘤模型中评估了ANV600的单药及联合药效： 1. 单药治疗剂量：剂量设置：0.03 mg/kg、0.1 mg/kg及0.2 mg/kg。药效结果：在B16F10黑色素瘤及MC38结肠癌模型中，0.2 mg/kg（静脉注射，第0、3天给药）诱导了最强烈的肿瘤生长抑制（TGI）。在B16F10模型中，TGI显著优于相同剂量的非靶向对照物。 2. 联合用药增效：方案：ANV600 (0.2 mg/kg) 联合 PD-1抑制剂 (10 mg/kg，腹腔注射，第0、3、7天给药)。结果：在对PD-1单药不敏感的模型中，联合治疗组实现了几乎完全的肿瘤消退，其抗肿瘤反应呈现明显的加成或协同效应。 3. TILs重编程：流式细胞术显示，0.2 mg/kg剂量的ANV600能显著扩增肿瘤内的CD8+ T细胞（特别是Tcex和Tpex亚群），同时不引起Treg细胞的显著增加。四、肿瘤原位激活机制研究团队通过FTY720（一种抑制淋巴细胞从淋巴结流出的药物）封闭实验发现： ANV600的抗肿瘤效力主要驱动自肿瘤微环境内已存在的驻留T细胞。这意味着该药物能够有效逆转TME内的免疫耗竭状态，通过“唤醒”已存在的肿瘤特异性T细胞群，而非单纯依赖外周血免疫细胞的募集。五、安全性数据与临床转化1. 毒性监测：在临床前剂量强度试验中，ANV419 (与ANV600的IL2 端完全一样)在猴的最高剂量（0.3 mg/kg）下未引发明显的副作用，ANV600 在小鼠中给予0.2 mg/kg 剂量下也未观察到明显的体重减轻。体重：实验动物体重保持稳定，未出现类似传统IL-2导致的急性体重下降。血管损害：组织学检查未观察到肺水肿或血管渗漏综合征（VLS）的相关指征。目前，ANV600已正式进入临床评估阶段：试验编号：NCT06470763（EXPAND-1研究）研究设计：针对晚期实体瘤患者的Phase I/II期临床研究。主要终点：评估ANV600作为单药，以及与帕博利珠单抗（Pembrolizumab）联用的安全性、耐受性及剂量限制性毒性（DLT）。总结 ANV600的研究成果为克服IL-2类药物的剂量限制毒性提供了验证性路径。通过靶向PD-1非阻断表位的“顺式激活”策略，ANV600有望在PD-1治疗耐药的患者中提供全新的治疗方案，并与现有的免疫检查点疗法实现深度协同。风险提示：药物研发具有高风险性，临床试验结果存在不确定性。本文仅供科研及医疗专业人士参考，不作为临床诊疗依据。请患者及其家属理性看待研发进展，并遵医嘱进行治疗。参考文献： Patrizia Murer, et al.ANV600 is a novel PD-1 targeted IL-2Rβγ agonist that selectively expands tumor antigen-specific T cells and potentiates PD-1 checkpoint inhibitor therapy. JITC 2025. SITC 2024, Poster # 954.

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

100 项与 ANV-419 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床2期	西班牙	Vall d'Hebron Institut d'Oncologia	2025-01-15
宫颈癌	临床2期	西班牙	Vall d'Hebron Institut d'Oncologia	2025-01-15
晚期恶性实体瘤	临床2期	美国	Anaveon AG	2022-12-16
晚期恶性实体瘤	临床2期	法国	Anaveon AG	2022-12-16
晚期恶性实体瘤	临床2期	德国	Anaveon AG	2022-12-16
晚期恶性实体瘤	临床2期	意大利	Anaveon AG	2022-12-16
晚期恶性实体瘤	临床2期	西班牙	Anaveon AG	2022-12-16
皮肤黑色素瘤	临床2期	美国	Anaveon AG	2022-12-16
皮肤黑色素瘤	临床2期	法国	Anaveon AG	2022-12-16
皮肤黑色素瘤	临床2期	德国	Anaveon AG	2022-12-16

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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


NCT05578872 (CTgov)	临床1/2期	皮肤黑色素瘤 \| 晚期恶性实体瘤 \| 转移性黑色素瘤 ... 更多	29	ANV419 (ANV419 Single Agent, Low Dose)	壓顧網繭窪衊觸觸夢衊 = 顧積夢餘憲膚壓憲遞糧積鏇糧鹽鹹鹽衊構製鑰 (憲構夢範鑰願夢範淵衊, 夢壓鬱鹹積窪願衊醖簾 ~ 簾鹽醖製衊衊鹽構鑰淵) 更多	-	2025-08-26
				ANV419 (ANV419 Single Agent, High Dose)	壓顧網繭窪衊觸觸夢衊 = 壓醖廠夢鬱艱淵簾繭艱積鏇糧鹽鹹鹽衊構製鑰 (憲構夢範鑰願夢範淵衊, 鬱鹽膚願鹽夢夢衊製襯 ~ 壓衊鬱觸網淵繭構築醖) 更多
NCT04855929 (ANV419-001, Pubmed)	临床1期	晚期恶性实体瘤	-	ANV419	艱鹹鹹獵鬱簾遞築網繭(選蓋醖醖鹹遞築鏇鑰蓋) = 鬱壓艱範衊糧製艱壓鬱壓鹽衊餘鹽糧齋鬱鬱廠 (觸艱淵鏇鏇齋鑰繭鏇憲 ) 更多	积极	2023-11-01
NCT04855929 (ANV419-001, Corporate Publications) 人工标引	临床1/2期	肿瘤	26	ANV-419 (Single patient cohort)	-	积极	2022-09-10
				ANV-419 (3+3 cohort Dose Expansion)	艱鏇淵觸糧鹹鏇選繭構(憲醖窪齋窪壓淵醖築顧) = 憲網鏇遞膚膚顧選蓋簾觸鹽築築餘範製獵醖淵 (遞網積選範築齋願繭蓋 ) 更多
NCT04855929 (ANV419-001, AACR2022)	临床1/2期	肿瘤	-	ANV419	壓遞網餘窪膚蓋窪築鹽(積鹽憲製繭獵醖築構餘) = 鹹襯鬱憲簾製繭鏇觸鏇獵築廠積鑰願襯鏇餘淵 (壓廠鏇範範艱鏇繭鏇鏇 ) 更多	-	2022-06-15
NCT04855929 (ANV419-001, ASCO2022) 人工标引	临床1/2期	HR阳性/HER2低表达实体瘤	13	ANV419	鹽淵淵遞願齋齋壓鏇蓋(繭醖蓋鑰鹽鹹選糧衊窪) = 鬱鏇衊夢鹽鑰觸襯蓋鑰遞鑰簾窪築醖蓋鏇獵鹹 (遞範構淵膚窪廠顧憲鏇 ) 更多	积极	2022-06-02
SITC2021	临床1期	-	2	ANV419 0.03 mg/kg	簾鏇鹽簾鬱鏇膚糧鬱艱(範鑰鬱壓積觸築齋鹹構) = mild systemic inflammatory response was observed at 0.3 mg/kg evidenced by a transient increase of CRP on days 4 and 19 餘範範遞鹹廠鹹鹽繭鹹 (壓製糧糧簾夢壓遞繭構 ) 更多	积极	2021-11-10
				ANV419 0.1 mg/kg