The Efficacy of T-regulatory Cell Depletion With E7777 Combined With Immune Checkpoint Inhibitor, Pembrolizumab, in Recurrent or Metastatic Solid Tumors: Phase I/II Study

Epithelial ovarian cancer (OC) is the most lethal gynecologic cancer: nearly 22,000 women are diagnosed with OC in the US annually and 63% are expected to die from their disease. The 5-year overall survival rate is unacceptably low at 20-30%, with > 50% of patients experiencing recurrence of their disease. Recurrent, platinum-resistant OC is characterized by a low response to chemotherapy (<10-15%) and poor prognosis, with overall survival estimated to be <12 months. Thus, there is an urgent need to identify novel therapies to improve outcomes for patients with recurrent, platinum resistant OC. The primary focus in this trial is targeting tumor associated immunosuppressive T-regs with E7777 combined with PD-1 inhibitor, pembrolizumab. This trial will enroll patients with solid tumors in the dose escalation portion and specified cohorts in the dose expansion portion. In the Phase I portion, 18-30 patients will be enrolled. In the dose expansion portion, approximately 40 patients (20 in each cohort) will be enrolled. Given the relatively poor prognosis and limited treatment options for these patients, this population is considered appropriate for trials of novel therapeutic candidates.

开始日期2022-09-30

申办/合作机构

University of Pittsburgh

[+1]

NCT04855253 / Recruiting临床1/2期IIT

Phase I/II Trial Using E7777 to Enhance Regulatory T-Cell Depletion Prior to Tisagenlecleucel (Kymriah) Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

This is a single institution Phase I study to determine the maximum tolerated dose (MTD) of E7777 when given prior to cyclophosphamide/fludarabine (CY/Flu) lymphodepletion (LD) chemotherapy and Kymriah, a commercial tisagenlecleucel product, for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are at a higher risk for failure of CAR-T therapy.

开始日期2021-06-09

申办/合作机构

University of Minnesota Masonic Cancer Center

NCT05137847 / CompletedN/A

Post-marketing Observational Study of Remitoro® Intravenous Injection 300 μg - Safety of Remitoro in Patients With Recurrent or Refractory Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma (All Case Study)

The primary purpose of the study is to investigate the incidence of adverse drug reactions (ADRs) (ADR of special interest: capillary leak syndrome, infusion reaction, rhabdomyolysis, myelosuppression, infection, hepatic dysfunction, visual impairment/color blindness, ischemic heart disease/arrhythmia/cardiac failure, and severe skin disorders).

开始日期2021-05-24

申办/合作机构

Eisai, Inc.

100 项与地尼白介素2 相关的临床结果

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100 项与地尼白介素2 相关的转化医学

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100 项与地尼白介素2 相关的专利（医药）

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项与地尼白介素2 相关的文献（医药）

2023-12-06·Advances in Hematology

Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease

Review

作者: Chattaraj, Asmi ; Laek, Babray ; Khan, Rafiullah ; Wahab, Ahsan ; Proskuriakova, Ekaterina ; Ali, Rimsha ; Garg, Chandi ; Shah, Mitali ; Kovalenko, Iuliia ; Seyedroudbari, Sara ; Golubykh, Konstantin ; Saleem, Tabinda ; Mirza, Taaha

Background. Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant. The mainstay of treatment is corticosteroids, which are ineffective in 30–50% of cases. Steroid-refractory GVHD (SR-GVHD) confers a poor prognosis, with high mortality rates despite appropriate therapy. While there is no reliable treatment for SR-GVHD, a variety of novel therapeutic options are slowly emerging and have yet to be examined simultaneously. Objectives. This review evaluates the potential of novel therapeutic options, as well as their efficacy and safety, for the treatment of SR-GVHD. Study Design. The literature search was conducted in PubMed, Cochrane, and Embase, employing MeSH terms and keywords. The studies had to be prospective phases 1, 2, or 3. We excluded retrospective and nonoriginal studies. Results. While the only approved drug for acute GVHD is ruxolitinib with an impressive overall response rate of 73.2% and a complete response of 56.3%, several monoclonal antibodies and other agents are currently under investigation, offering promising results. These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin. However, the toxicities associated with these novel drugs need further investigation. For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. Conclusion. While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future.

2023-07-24·JCI insight

T cell activation is insufficient to drive SIV disease progression.

Article

作者: Martinez Sosa, Natalie ; Krampe, Noah ; Kleinman, Adam J ; Lackner, Andrew A ; Sivanandham, Ranjit ; Martin, Kathryn J ; Sette, Paola ; Ribeiro, Ruy M ; He, Tianyu ; Brocca-Cofano, Egidio ; Raehtz, Kevin D ; Landay, Alan L ; Sivanandham, Sindhuja ; Gautam, Rajeev ; Pandrea, Ivona ; Valentine, Audrey ; Apetrei, Cristian ; Gaufin, Thaidra

Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury. We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation. Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.

2023-07-01·FEBS open bio

CCR4-IL2 bispecific immunotoxin is more effective than brentuximab for targeted therapy of cutaneous T-cell lymphoma in a mouse CTCL model.

Article

作者: Wang, Zhirui ; Mintzlaff, Danielle ; Ma, Jihong ; Gao, Dexiang ; Wang, Zhaohui ; Pomfret, Elizabeth A ; Zhang, Huiping ; Haverkos, Bradley M ; Lucia, M Scott ; Ramakrishna, Rashmi ; Mathes, David W

Cutaneous T-cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis fungoides and Sezary syndrome are approximately 30%, and none of these treatments are thought to be curative. C-C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We developed a novel CCR4-IL2 bispecific immunotoxin (CCR4-IL2 IT) targeting both CCR4 and CD25. CCR4-IL2 IT demonstrated superior efficacy against CCR4⁺ CD25⁺ CD30⁺ CTCL in an immunodeficient NSG mouse tumor model. Investigative New Drug-enabling studies of CCR4-IL2 IT are ongoing, including Good Manufacturing Practice production and toxicology studies. In this study, we compared the in vivo efficacy of CCR4-IL2 IT versus the US Food and Drug Administration-approved drug, brentuximab, using an immunodeficient mouse CTCL model. We demonstrated that CCR4-IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4-IL2 IT and brentuximab was more effective than brentuximab or CCR4-IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4-IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment.

项与地尼白介素2 相关的新闻（医药）

2024-04-30

·PRNewswire

Citius Pharmaceuticals Announces Closing of $15 Million Registered Direct Offering

CRANFORD, N.J., April 30, 2024 /PRNewswire/ -- Citius Pharmaceuticals Inc. (Nasdaq: CTXR) ("Citius" or the "Company"), a late-stage biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products, today announced that it has closed its previously announced registered direct offering for the purchase of an aggregate of 21,428,574 shares of its common stock and accompanying warrants to purchase up to an aggregate of 21,428,574 shares of its common stock, at a purchase price of $0.70 per share and accompanying warrant. The warrants have an exercise price of $0.75 per share, will be exercisable six months from the date of issuance, and will expire five years from the initial exercise date. H.C. Wainwright & Co. acted as the exclusive placement agent for the offering. The aggregate gross proceeds to the Company from the offering were approximately $15 million, before deducting the placement agent fees and other offering expenses payable by the Company. Citius currently intends to use the net proceeds from the offering for general corporate purposes, including pre-clinical and clinical development of our product candidates and working capital and capital expenditures. The securities described above were offered pursuant to a "shelf" registration statement (File No. 333-277319) filed with the Securities and Exchange Commission ("SEC") on February 23, 2024 and declared effective on March 1, 2024. The offering was made only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. The prospectus supplement and the accompanying prospectus relating to the securities offered was filed with the SEC and is available at the SEC's website at . Electronic copies of the prospectus supplement and the accompanying prospectus relating to the securities being offered may also be obtained by contacting H.C. Wainwright & Co., LLC at 430 Park Avenue, 3rd Floor, New York, NY 10022, by telephone at (212) 856-5711 or e-mail at [email protected]. This press release shall not constitute an offer to sell or the solicitation of an offer to buy any of the securities described herein, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or jurisdiction. About Citius Pharmaceuticals, Inc. Citius is a late-stage biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products. The Company's diversified pipeline includes two late-stage product candidates. The Biologics License Application for LYMPHIR™, a novel IL-2R immunotherapy for an initial indication in cutaneous T-cell lymphoma, is currently under review by the FDA with August 13, 2024 assigned as the PDUFA target action date. Citius previously announced plans to form Citius Oncology, a standalone publicly traded company with LYMPHIR as its primary asset. LYMPHIR received orphan drug designation by the FDA for the treatment of CTCL and PTCL. In addition, Citius completed enrollment in its Phase 2b trial of CITI-002 (Halo-Lido), a topical formulation for the relief of hemorrhoids. For more information, please visit . Forward Looking Statements This press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "plan," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price, and includes all statements related to the intended use of net proceeds from the offering. Factors that could cause actual results to differ materially from those currently anticipated are: risks relating to the results of research and development activities, including those from existing and new pipeline assets; uncertainties relating to preclinical and clinical testing; the early stage of products under development; our need for substantial additional funds; our ability to commercialize our products if approved by the FDA; our dependence on third-party suppliers; our ability to procure cGMP commercial-scale supply; the estimated markets for our product candidates and the acceptance thereof by any market; the ability of our product candidates to impact the quality of life of our target patient populations; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; market and other conditions; our ability to attract, integrate, and retain key personnel; risks related to our growth strategy; patent and intellectual property matters; our ability to identify, acquire, close and integrate product candidates and companies successfully and on a timely basis; government regulation; competition; as well as other risks described in our SEC filings. These risks have been and may be further impacted by Covid-19 and could be impacted by any future public health risks. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our SEC filings which are available on the SEC's website at , including in our Annual Report on Form 10-K for the year ended September 30, 2023, filed with the SEC on December 29, 2023, and updated by our subsequent filings with the SEC. These forward-looking statements speak only as of the date hereof, and we expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law. Investor Contact: Ilanit Allen [email protected] 908-967-6677 x113 Media Contact: STiR-communications Greg Salsburg [email protected] SOURCE Citius Pharmaceuticals, Inc.

孤儿药临床2期免疫疗法

2024-04-11

·BioSpace

Citius Pharmaceuticals Announces Addition of City of Hope to UMN's Phase 1 Trial of LYMPHIR in Combination with CAR-T for the Treatment of B-Cell Lymphoma

National Cancer Institute (NCI)-designated research and treatment center City of Hope, in Duarte, CA, to participate in the University of Minnesota (UMN) Masonic Cancer Center's ongoing Phase 1 trial to determine the maximum tolerated dose of LYMPHIR plus CAR-T therapy CRANFORD, N.J., April 11, 2024 /PRNewswire/ -- Citius Pharmaceuticals, Inc. ("Citius" or the "Company") (Nasdaq: CTXR), a late-stage biopharmaceutical company developing and commercializing first-in-class critical care products, today announced that the University of Minnesota Masonic Cancer Center intends to expand their ongoing investigator-initiated Phase 1 trial of LYMPHIR™ (denileukin diftitox) in combination with FDA-approved CAR-T products for the treatment of B-cell lymphomas. The ongoing study, led by Dr. Veronika Bachanova at the University of Minnesota (UMN), will include an additional study site at City of Hope (COH), a world-renowned cancer treatment and research institution, with Dr. Matthew Mei as the principal site investigator at COH. City of Hope is one of only 53 National Cancer Institute (NCI)-designated comprehensive cancer centers in the U.S. "We are encouraged by the scientific community's interest in exploring the potential benefits of LYMPHIR beyond cutaneous T-cell lymphoma, for which a Biologics License Application is currently under review by the FDA. We are very excited to support UMN's expansion of its study to City of Hope as distinguished oncologists Dr. Bachanova and Dr. Mei conduct innovative research to evaluate LYMPHIR in combination with CAR-T treatment," stated Dr. Myron Czuczman, Chief Medical Officer of Citius. "This first-of-its-kind study will evaluate the potential value that transient depletion of T-regs within the tumor microenvironment by LYMPHIR has upon CAR-T-based anti-tumor activity," added Dr. Czuczman. "This trial is designed to augment lymphodepletion prior to CAR-T cells by administration of targeted immunotoxin against IL-2 receptor-positive regulatory T-cells. The lymphodepleting chemotherapy augmented with LYMPHIR was combined with all three standard of care CAR-T products for diffuse large B-cell lymphomas in second or third line of therapy. We look forward to welcoming patients from City of Hope as we expand the trial and evaluate the maximum tolerated dose," stated principal investigator Veronika Bachanova, MD, PhD, Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota. Citius is collaborating with the University of Minnesota (UMN) in this investigator-initiated study. This Phase 1 dose-finding study to evaluate LYMPHIR prior to CAR-T therapies tisagenlecleucel (KYMRIAH®), axicabtagene ciloleucel (YESCARTA®), or lisocabtagene maraleucel/BREYANZI®), in patients with B-cell lymphomas (BCL) (NCT0485525) was initiated in May 2021 and has been expanded to include City of Hope. Enrollment is underway for patients diagnosed with relapsed or refractory BCL, for which treatment with CAR-Ts is planned, and who are considered at high risk for progression after CAR-T therapy. About University of Minnesota Masonic Cancer Center The Masonic Cancer Center serves as the hub for cancer research at the University of Minnesota. More than 600 members apply their expertise to the broad problem of cancer with research in cancer causes, prevention, treatment, outcomes, and survivorship. Founded in 1991, the cancer center became a National Cancer Institute (NCI) designated Comprehensive Cancer Center in 1998, one of only 53 institutions in the United States and two in Minnesota to hold that designation. About City of Hope City of Hope, a National Cancer Institute (NCI)-designated comprehensive cancer center, is a world-renowned pioneer in cancer research, treatment and prevention. City of Hope's mission is to deliver the cures of tomorrow to the people who need them today. Founded in 1913, City of Hope has grown into one of the largest cancer research and treatment organizations in the U.S. and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. City of Hope brings a uniquely integrated model to patients spanning cancer care, research and development, academics and training, and innovation initiatives. City of Hope's growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and treatment facilities in Atlanta, Chicago and Phoenix. City of Hope's affiliated group of organizations includes Translational Genomics Research Institute and AccessHope™. About Citius Pharmaceuticals, Inc. Citius Pharma is a late-stage biopharmaceutical company dedicated to the development and commercialization of first-in-class critical care products. The Company's diversified pipeline includes two late-stage product candidates. At the end of 2023, Citius completed enrollment in a Phase 3 pivotal superiority trial of Mino-Lok®, an antibiotic lock solution to salvage catheters in patients with catheter-related bloodstream infections. Citius resubmitted the Biologics License Application for LYMPHIR, a novel IL-2R immunotherapy for an initial indication in cutaneous T-cell lymphoma, in early 2024, and announced plans to form Citius Oncology, a standalone publicly traded company with LYMPHIR as its primary asset. LYMPHIR received orphan drug designation by the FDA for the treatment of CTCL and PTCL. In addition, Citius completed enrollment in its Phase 2b trial of CITI-002 (Halo-Lido), a topical formulation for the relief of hemorrhoids. For more information, please visit . Forward-Looking Statements This press release may contain "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Such statements are made based on our expectations and beliefs concerning future events impacting Citius. You can identify these statements by the fact that they use words such as "will," "anticipate," "estimate," "expect," "plan," "should," and "may" and other words and terms of similar meaning or use of future dates. Forward-looking statements are based on management's current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated are: risks relating to the results of research and development activities, including those from existing and new pipeline assets; uncertainties relating to preclinical and clinical testing; the early stage of products under development; our need for substantial additional funds; our ability to commercialize our products if approved by the FDA; our dependence on third-party suppliers; our ability to procure cGMP commercial-scale supply; the estimated markets for our product candidates and the acceptance thereof by any market; the ability of our product candidates to impact the quality of life of our target patient populations; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; market and other conditions; our ability to attract, integrate, and retain key personnel; risks related to our growth strategy; patent and intellectual property matters; our ability to identify, acquire, close and integrate product candidates and companies successfully and on a timely basis; government regulation; competition; as well as other risks described in our SEC filings. These risks have been and may be further impacted by Covid-19 and could be impacted by any future public health risks. Accordingly, these forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. Risks regarding our business are described in detail in our Securities and Exchange Commission ("SEC") filings which are available on the SEC's website at , including in our Annual Report on Form 10-K for the year ended September 30, 2023, filed with the SEC on December 29, 2023, and updated by our subsequent filings with the Securities and Exchange Commission. These forward-looking statements speak only as of the date hereof, and we expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as required by law. KYMRIAH® is a registered trademark of Novartis Pharmaceuticals Corporation. YESCARTA® is a registered trademark of Kite Pharma, Inc., a Gilead Sciences, Inc. company. BREYANZI® is a registered trademark of Juno Therapeutics, Inc., a Bristol Myers Squibb company. Investor Contact: Ilanit Allen ir@citiuspharma.com 908-967-6677 x113 Media Contact: STiR-communications Greg Salsburg Greg@STiR-communications.com Company Codes: NASDAQ-SMALL:CTXR

免疫疗法临床1期临床3期孤儿药临床2期

2024-03-26

·CPHI制药在线

改良版新药BLA申请获受理，IL-2新药进展还有哪些？

关注并星标智药公会近日，Citius Pharmaceuticals宣布，FDA已接受其药物 Lymphir的生物制品许可申请（BLA），用于至少经过一次全身性治疗的复发或难治性皮肤T细胞淋巴瘤（CTCL）的治疗。该申请的PDUFA目标日期为2024年8月13日。 Lymphir是一种将白喉毒素片段与白细胞介素-2（IL-2）受体结合域相结合的重组融合蛋白，其通过与细胞表面的IL-2受体结合，来精确递送白喉毒素，使进入细胞的白喉毒素片段抑制恶性T细胞的蛋白质合成。此次BLA申请主要基于一项关键性III期研究。该试验结果显示，经独立审查委员会（IRC）评估，Lymphir达到36.2%的客观缓解率（ORR）。研究者进行的效力分析发现的ORR为42.3%。值得一提的是，Lymphir是抗肿瘤药物Onak的一种纯化重组制剂，通过对Onak的原始配方进行改进，Lymphir具有更高的纯度以及生物活性。Onak由卫材公司研发，于1999年获FDA批准上市，后来因血管渗漏等安全性问题自愿撤市。 IL-2的双面性 IL-2是免疫系统中一类重要的细胞生长因子，本质上来说，IL-2是一种在维持T淋巴细胞和NK细胞的正常功能中起着重要作用的球状糖蛋白。随着研究的深入，人们发现IL-2具有双重活性：在高剂量环境下，IL-2可促进效应T细胞增殖，驱动抗癌活性；低剂量IL-2则会选择性激活调节性T细胞（Tregs），从而抑制免疫激活。也正是这个原因，使得IL-2药物研发存在很大困难。其中一个挑战便是如何使IL-2特异性激活一个T细胞群（效应T细胞）而非另一个T细胞群（Tregs）。后来的研究发现，IL-2的双面性与IL-2结合的受体有着密切关系，IL2的受体复合物有三聚体形式（由α、β和γ链组成）和二聚体形式（仅由β和γ链组成）。其中三聚体主要表达在活化的T细胞与Treg细胞表面，与IL-2的亲和力最强。因此只需低剂量的IL-2即可激活下游信号通路，促进免疫细胞的增殖与活化。二聚体形式的受体复合物存在于记忆性T细胞和NK细胞表面，以中亲和力结合IL-2，因此需要高剂量的IL-2才能激活下游信号通路。目前，大部分研发者通过改造IL-2结构以改变对三聚体受体复合物的亲和力，导向优先结合二聚体，以激发IL-2的抗肿瘤潜能。BMS、赛诺菲、罗氏等纷纷在这一领域布局。 IL-2药物研发进展 Nektar/BMS Nektar是一家深度聚焦IL-2药物研发的公司。其开发的第一款IL-2药物NKTR-214曾得到BMS的青睐。 NKTR-214是一款新一代PEG化的IL-2药物，创新性地将6个PEG分子与IL-2相连形成NKTR-214前药，在注射入体内后，PEG基团不可逆地脱落并形成具有药物活性的2-PEG和1-PEG活性成分。二者对IL-2R二聚体受体具有较高亲和力，而对IL-2R三聚体受体亲和力较低，从而在刺激免疫系统的同时减少了对Tregs增殖的促进作用。 2018年，BMS与Nektar达成协议，将共同挖掘NKTR-214联用Opdivo或Opdivo+Yervoy在多种类型肿瘤中的治疗潜力，不过这一合作并不顺利。 2022年3月，Nektar/BMS共同宣布NKTR-214联合Opdivo治疗不可切除或转移性黑色素瘤的III期PIVOT-12研究失败；2022年4月，Nektar/BMS宣布NKTR-214+Opdivo治疗肾细胞癌和膀胱癌的两项临床研究亦失败。至此，两家公司决定终止NKTR-214+Opdivo的全球临床开发计划。 Synthorx/赛诺菲 2019年12月，赛诺菲以25亿美元收购Synthorx，同时获得了其工程化偏向性IL-2抗体药物THOR-707。对于THOR-707，赛诺菲曾把它看作是"一种有可能成为下一代免疫肿瘤联合疗法基础的分子"。不过在THOR-707联合PD-1抗体Opdivo，治疗转移性黑色素瘤的III期临床研究中，未达到PFS和ORR的主要终点，赛诺菲宣布终止THOR-707的开发。罗氏罗氏在IL-2药物研发方面独辟蹊径。它将偏向性IL-2与一种具有阻断功能的、高亲和力的PD-1抗体融合，产生PD-1/IL-2v抗体融合蛋白。PD-1/IL2v与PD-1和IL-2Rβγ的顺式结合恢复了在没有CD25（IL-2Rɑ）结合的情况下可以将干细胞样CD8+T细胞分化为更好效应器的能力，并提供了更好的疗效。其开发的PD-1/IL-2v抗体融合蛋白的初步数据显示，该产品不仅能有效解除PD-1免疫抑制，还能够延长IL-2半衰期、激活IL-2信号传导通路并扩增T细胞，达到强效歼灭肿瘤细胞的效果。在国内，针对IL-2靶点的布局，以恒瑞医药、信达生物、君实生物等为代表。恒瑞医药有两款IL-2药物在研，分别是SHR-1916和RS2102。SHR-1916采用PEG进行修饰，一方面延长了半衰期，另一方面加入的PEG基团能够减弱或阻止IL-2与受体三聚体的相互作用。SHR-1916通过激活JAK1/JAK3/STAT5信号通路，促进CD8+T和NK细胞增殖，发挥抗肿瘤作用。恒瑞的另一款IL-2产品RS2102开发的方向则是聚焦于自免疾病。信达生物的IBI363是一款抗PD-1/IL-2双特异性抗体融合蛋白。其IL-2臂采用α-biased设计，在提高疗效的同时降低IL-2相关毒性，而PD-1结合臂可以实现对PD-1的阻断和IL-2的选择性递送。因此，IBI363具有同时阻断PD-1/PD-L1通路和激活IL-2通路两项功能，可以更精确有效地实现对肿瘤特异性T细胞的靶向和激活。在临床前模型中，IBI363安全性良好。目前正在中国和澳大利亚进行临床I期研究。在IL-2药物研发领域，君实生物主要依赖外部引进。2020年8月，君实生物以2100万元预付款，9.38亿元里程碑金额，获得志道生物IL-2药物LTC002全球范围内的独占许可。2020年9月，君实生物又从Anwita引进Anti-HSA-IL2Nα系列产品和相关ANWITA技术和知识产权，涉及IL-2Nα蛋白、Anti-HSA-IL-2Nα融合蛋白及衍生物。 IL-2最早于1976年被发现，事实上已经是一个比较成熟的抗癌靶点。随着技术的进步，产业界已经找到了一些方法和途径来增强IL-2对CD8+T细胞的激活并减少或阻断对Tregs的激活，期待IL-2疗法在免疫治疗领域真正发光发热。主要参考资料： 1.https://rapport.bio/all-stories/nektar-il-2-legacy-two-sides-failure. 2.H. Søndergaard & K. Skak. IL-21: roles in immunopathology and cancer therapy. Immunopharmacology 20092. Josef S. Smolen, Peter E. Lipsky. Contemporary Targeted Therapies in Rheumatology 2007. 3.https://www.prnewswire.com/news-releases/citius-pharmaceuticals-announces-fda-acceptance-of-the-bla-resubmission-of-lymphir-denileukin-diftitox-for-the-treatment-of-adults-with-relapsed-or-refractory-cutaneous-t-cell-lymphoma-302090911.html. 4.PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells. 【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床结果临床3期细胞疗法上市批准临床2期

100 项与地尼白介素2 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D03682	地尼白介素2	L01XX29	DB00004

研发状态

适应症	最高研发状态	国家/地区	公司
外周T细胞淋巴瘤	批准上市	日本更多	TSD Japan, Inc. 更多
皮肤T细胞淋巴瘤	批准上市	美国更多	Eisai, Inc. 更多
实体瘤	临床前	美国更多	Dr. Reddy's Laboratories Ltd. 更多
头颈部肿瘤	终止	美国更多	Ligand Pharmaceuticals, Inc. 更多
慢性淋巴细胞白血病	无进展	美国更多	Eisai, Inc. 更多

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临床结果

适应症

分期

评价

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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


NCT01871727 (Pivotal Study 302, ASH2022) 人工标引	临床3期	皮肤难治性T细胞淋巴瘤	112	E7777	築鹽築鏇築製鹽憲觸積(鑰淵蓋艱範獵網築衊遞) = 願壓齋窪鑰壓夢遞構窪鹽壓襯築衊觸餘獵憲廠 (衊憲蓋糧鹽艱膚衊廠廠, 25.0 ~ 48.7) 更多	积极	2022-11-15
NCT01127451 (CTgov)	临床2期	恶性黑色素瘤IV期	75	Denileukin diftitox (Denileukin Diftitox on Days 1 to 4)	壓鏇壓餘簾鏇網繭憲蓋(鬱襯選艱壓遞願夢廠鏇) = 憲選遞鑰艱夢鹽廠憲簾艱遞壓顧艱鏇積選夢鹹 (遞獵獵願廠齋餘艱網顧, 製糧窪範構獵選廠衊衊 ~ 淵憲廠顧顧鬱繭鏇廠網) 更多	-	2022-04-13
				Denileukin diftitox (Denileukin Diftitox on Days 1, 8, and 15)	壓鏇壓餘簾鏇網繭憲蓋(鬱襯選艱壓遞願夢廠鏇) = 遞鬱構選製襯壓獵積夢艱遞壓顧艱鏇積選夢鹹 (遞獵獵願廠齋餘艱網顧, 艱選醖鹽範艱淵鑰製餘 ~ 艱網簾鬱製繭窪齋觸積) 更多
NCT01871727 (Lead-In, Biospace) 人工标引	临床3期	皮肤T细胞淋巴瘤	71	E7777 (Independent (IRC) Stage I-III)	觸淵選艱繭艱鬱鹽鏇膚(窪夢餘鬱構鹹窪範顧衊) = 鹽糧窪齋鬱鑰鑰遞窪獵餘鬱廠鹽願糧遞顧壓製 (構繭齋獵選積鑰鏇壓顧, 25.0 ~ 48.7) 更多	积极	2022-04-06
				E7777 (Investigator Stage I-III)	觸淵選艱繭艱鬱鹽鏇膚(窪夢餘鬱構鹹窪範顧衊) = 積艱糧鬱獵製鏇糧憲觸餘鬱廠鹽願糧遞顧壓製 (構繭齋獵選積鑰鏇壓顧, 30.6 ~ 54.6) 更多
NCT02676778 (CTgov)	临床2期	外周T细胞淋巴瘤 \| 皮肤T细胞淋巴瘤	45	E7777+PTCL (PTCL: E7777 9 mcg/kg/Day)	蓋鹽繭醖襯願夢齋襯遞(鏇蓋簾壓襯衊製餘遞餘) = 觸獵顧積構鏇鑰範鬱觸鹽積糧範壓獵衊糧選壓 (襯鏇構憲衊壓艱鑰衊廠, 鹹鬱鹽淵選顧鬱夢膚觸 ~ 廠餘衊鏇襯齋網積鹹鹹) 更多	-	2021-07-15
				E7777 (CTCL: E7777 9 mcg/kg/Day)	蓋鹽繭醖襯願夢齋襯遞(鏇蓋簾壓襯衊製餘遞餘) = 獵網選鬱積網齋獵築襯鹽積糧範壓獵衊糧選壓 (襯鏇構憲衊壓艱鑰衊廠, 衊鬱廠襯壓襯夢齋積膚 ~ 襯夢衊艱構製衊鬱觸齋) 更多
NCT00515528 (CTgov)	临床2期	转移性黑色素瘤	17	4-peptide melanoma vaccine (Vaccine Alone)	艱鏇網壓憲觸選夢糧繭(壓鏇網糧繭廠獵鹹顧鏇) = 鹹膚憲餘範襯壓蓋糧鹽鏇憲願襯鑰艱艱鹽願膚 (憲膚構窪膚艱壓鏇淵願, 選憲蓋觸選鹹膚襯選淵 ~ 築餘願膚鹽淵網蓋鏇齋) 更多	-	2020-10-29
				Ontak+4-peptide melanoma vaccine (Vaccine Plus Ontak)	艱鏇網壓憲觸選夢糧繭(壓鏇網糧繭廠獵鹹顧鏇) = 遞齋壓鬱壓選簾蓋顧蓋鏇憲願襯鑰艱艱鹽願膚 (憲膚構窪膚艱壓鏇淵願, 膚繭構鑰繭選觸構齋選 ~ 鹽範糧衊鑰範艱膚廠遞) 更多
NCT00632827 (CTgov)	临床2期	外周T细胞淋巴瘤	21	Granulocyte-colony stimulating factor (G-CSF)+Denileukin diftitox+etoposide+cyclophosphamide+Carmustine+Leucovorin+doxorubicin hydrochloride+Gemcitabine+Navelbine+Vincristine+Methotrexate+Cytarabine	壓願獵鑰蓋淵願淵繭襯(獵簾壓鏇獵選範齋遞齋) = 膚窪糧構鹽鬱餘簾衊壓衊鬱範夢觸鏇糧繭糧膚 (獵鬱願壓齋積蓋遞齋襯, 顧鑰衊淵獵遞選鬱築築 ~ 築醖糧遞淵衊壓醖齋襯) 更多	-	2020-04-27
NCT00211185 (CTgov)	临床2期	外周T细胞淋巴瘤	49	Denileukin diftitox+Pegfilgrastim+Cyclophosphamide+Prednisone+Doxorubicin+Vincristine	積壓獵網衊淵構蓋鹹糧(觸製構觸製鹽製遞網襯) = 觸築鏇構齋糧製網遞簾廠顧網鬱衊鏇醖醖醖壓 (積膚繭鑰齋積壓衊簾構, 壓鹹夢蓋鬱製醖憲繭築 ~ 構糧願範餘繭憲顧鬱選) 更多	-	2020-03-18
NCT01401530 (CTgov)	临床1期	外周T细胞淋巴瘤	13	Denileukin Diftitox (Denileukin Diftitox)	選鹹積簾願艱範鑰鬱鏇(願餘蓋選顧鏇衊選夢壓) = 餘獵鹽糧願齋網齋襯壓醖觸遞鹽製網蓋餘鹽壓 (鏇顧餘淵顧鑰顧淵鏇鹽, 醖衊鏇餘積膚淵構鑰積 ~ 糧構鹹窪醖鑰繭膚簾獵)	-	2018-11-23
				Denileukin Diftitox (Cohort 1: 6 ug/kg/Day Denileukin Diftitox)	蓋廠鑰繭糧膚淵鏇選選(餘觸鹽鹹夢願鹹餘觸鑰) = 網淵願廠齋願選鏇蓋築膚網選範鑰鬱鹹網築餘 (憲願鹹窪窪艱鬱艱憲範, 齋糧壓齋淵糧蓋鏇願顧 ~ 淵衊夢願鑰觸襯夢製廠) 更多
NCT00425672 (CTgov)	临床1/2期	转移性乳腺癌 \| 3型乳腺癌 \| 男性乳腺肿瘤 ... 更多	15	ONTAK+flow cytometry	觸積構願廠壓襯獵網積(淵鏇膚窪製遞鹹選積觸) = 蓋鑰構簾淵願鏇夢製糧積網鬱廠選積繭廠鏇遞 (窪齋蓋鏇夢壓鬱觸鹹憲, 廠積醖築淵鑰鑰淵衊鏇 ~ 簾繭製憲膚簾構膚積築) 更多	-	2017-08-04
NCT00460109 (CTgov)	临床2期	滤泡性淋巴瘤	24	denileukin diftitox+Rituximab	窪鏇鹽壓選襯製鏇構糧(鑰壓鹽餘構齋願夢遞齋) = 鹽鹽鬱製獵醖顧繭網網鏇鑰壓製鹽膚遞糧繭糧 (鏇製鏇顧壓繭範獵憲築, 齋淵遞獵鑰範鹹鑰顧選 ~ 艱糧鏇繭鏇鏇壓鏇鏇網) 更多	-	2017-04-18