LMB-2(LMB-2) - 药物靶点：IL2RA_专利_临床

概要

基本信息

药物类型

抗体偶联毒素

别名

LMB-2A

靶点

IL2RA

作用方式

抑制剂

作用机制

IL2RA抑制剂(白细胞介素-2受体α链抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病+ [2]

在研适应症-

非在研适应症

急性淋巴细胞白血病成人T细胞白血病/淋巴瘤CD25阳性B细胞慢性淋巴细胞白血病+ [5]

原研机构

National Cancer Institute

在研机构-

非在研机构

National Cancer InstituteNational Institutes of Health Clinical Center

权益机构-

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

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关联

8

项与 LMB-2 相关的临床试验

NCT00924170

/ Completed临床1/2期IIT

Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia

BACKGROUND:
* Cluster of differentiation 25 (CD25) (p55, Tac or interleukin 2 receptor (IL2R) alpha) is strongly expressed in virtually 100% of patients with adult T-cell leukemia/lymphoma (ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy responding poorly to chemotherapy.
* In ATL, the humanized anti-CD25 monoclonal antibody (Mab) daclizumab produced 13-14% responses, and the anti-CD52 Mab Alemtuzumab (Campath-1H) produced response lasting greater than 2 months in 30% of 23 patients.
* LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb anti-Tac and truncated Pseudomonas exotoxin.
* In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD) of LMB-2 was 40 microg/Kg intravenous (IV) given every other day for 3 doses (every other day (QOD) times 3). LMB-2 induced greater than 90% tumor reduction rapidly in all 3 ATL patients on protocol, but achieved only 1 partial response due to rapid tumor progression and/or immunogenicity.
* In preclinical models, response from recombinant immunotoxins is limited by high concentrations of soluble receptor in the blood and especially in the interstitial space of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due to reduction of soluble receptor in tumor interstitium.
OBJECTIVES:
-To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate of major response lasting greater than 2 months, which may be an improvement over that demonstrated previously from Alemtuzumab (CAMPATH).
Secondary objectives:
* To determine the effect of 1 cycle of FC alone in ATL.
* To examine progression-free and overall survival in ATL after FC/LMB-2.
* Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor marker levels in the serum.
* To study the effects of LMB-2 plus FC on normal B- and T-cell subsets by fluorescence-activated cell sorting (FACS).
ELIGIBILITY:
* CD25 plus ATL, untreated or with prior therapy
* Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC), platelets and albumin at least 1000, 75,000, and 3.0.
DESIGN:
* Fludarabine 25 mg/m(2) IV days 1-3
* Cyclophosphamide 250 mg/m(2) IV days 1-3
* LMB-2 30-40 micro g/Kg IV days 3, 5 and 7.
* LMB-2 dose: Begin with 30 microg/Kg times 3. Escalate to 40 microg/Kg if dose limiting toxicity (DLT) in 0/3 or 1/6 at 30 microg/Kg. Continue at 40 microg/Kg if 0-1 of 6 have DLT at 40 microg/Kg.
* Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles of FC plus LMB-2 at minimum 20-day intervals.
* Accrual goals: 29-37 patients, which includes 4 replacements....

开始日期2008-10-31

申办/合作机构

National Cancer Institute

NCT00389506

/ WithdrawnN/AIIT

A Pilot Study of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for Treatment of CD25 Positive Hodgkin's Disease After Fludarabine and Cyclophosphamide

RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. LMB-2 immunotoxin can find cancer cells and kill them without harming normal cells. Giving fludarabine and cyclophosphamide followed by LMB-2 immunotoxin may kill more cancer cells.
PURPOSE: This clinical trial is studying how well giving fludarabine and cyclophosphamide followed by LMB-2 immunotoxin works in treating patients with Hodgkin's lymphoma.

开始日期2006-09-01

申办/合作机构

National Institutes of Health Clinical Center

[+1]

NCT00321555

/ Completed临床2期IIT

A Phase II Clinical Trial of Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin for CD25 Positive Hairy Cell Leukemia

Background:
* About 80% of patients with hairy cell leukemia (HCL) have tumor cells that have a protein on their surface called cluster of differentiation 25 (CD25).
* The experimental drug LMB-2 is a recombinant immunotoxin that has been shown to kill leukemia and lymphoma cells with the CD25 protein. (A recombinant immunotoxin is a genetically engineered drug that has two parts - a protein that binds or targets a cancer cell, and a toxin that kills the cancer cell to which it binds.)
Objectives:
* To evaluate the safety and effectiveness of LMB-2 in patients with HCL whose cancer cells contain the CD25 protein.
* To evaluate the effects of LMB-2 on the immune system, determine how the drug is metabolized by the body and examine its side effects.
Eligibility:
-Adults with hairy cell leukemia whose tumor cells have CD25 on their surface
Design:
* Up to 27 patients may be included in the study.
* Patients receive an infusion of LMB-2 through a vein every other day for three doses (days 1, 3, 5), constituting one treatment cycle.
* Patients may receive up to six treatment cycles every 4 weeks unless their cancer worsens or they develop unacceptable side effects.
* Blood is drawn weekly for various tests.
* Before each cycle and in follow-up visits, disease status is evaluated with a physical examination, blood tests, chest x-ray and electrocardiogram.
* Before the first cycle, patients may have a computed tomography (CT) scan, echocardiogram (heart ultrasound test) and bone marrow biopsy. With the patient's permission, these tests may be repeated before other cycles also.

开始日期2006-05-02

申办/合作机构

National Cancer Institute

100 项与 LMB-2 相关的临床结果

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100 项与 LMB-2 相关的转化医学

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100 项与 LMB-2 相关的专利（医药）

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27

项与 LMB-2 相关的文献（医药）

2021-05-01·Kidney international1区 · 医学

Glomerular filtrate affects the dynamics of podocyte detachment in a model of diffuse toxic podocytopathy

1区 · 医学

Article

作者: Saga, Nobuyuki ; Sakamoto, Kazuo ; Nagata, Michio ; Matsusaka, Taiji

Podocyte injury and subsequent detachment are hallmarks of progressive glomerulosclerosis. In addition to cell injury, unknown mechanical forces on the injured podocyte may promote detachment. To identify the nature of these mechanical forces, we studied the dynamics of podocyte detachment using sequential ultrastructural geometry analysis by transmission electron microscopy in NEP25, a mouse model of podocytopathy induced by anti-Tac(Fv)-PE38 (LMB2), a fusion protein attached to Pseudomonas exotoxin A, targeting CD25 on podocytes. After LMB2 injection, foot process effacement occurred on day three but detachment commenced on day eight and extended to day ten, reaching toward the urinary pole in clusters. Podocyte detachment was associated with foot process effacement covering over 60% of the glomerular basement membrane length. However, approximately 25% of glomeruli with diffuse (over 80%) foot process effacement showed no detachment. Blocking glomerular filtration via unilateral ureteral obstruction resulted in diffuse foot process effacement but no pseudocysts or detachment, whereas uninephrectomy increased pseudocysts and accelerated detachment, indicating that glomerular filtrate drives podocyte detachment via pseudocyst formation as a forerunner. Additionally, more detachment was observed in juxtamedullary glomeruli than in superficial glomeruli. Thus, glomerular filtrate drives the dynamics of podocyte detachment in this model of podocytopathy. Hence, foot process effacement may be a prerequisite allowing filtrate to generate local mechanical forces that expand the subpodocyte space forming pseudocysts, promote podocyte detachment and subsequent segmental sclerosis.

2019-09-01·Hypertension (Dallas, Tex. : 1979)1区 · 医学

Podocyte Injury Augments Intrarenal Angiotensin II Generation and Sodium Retention in a Megalin-Dependent Manner

1区 · 医学

Article

作者: Yanagita, Motoko ; Fujita, Toshiro ; Saito, Akihiko ; Ueda, Kohei ; Fukagawa, Masafumi ; Nishiyama, Akira ; Pastan, Ira ; Niimura, Fumio ; Matsusaka, Taiji ; Koizumi, Masahiro

We have previously shown that podocyte injury increases the glomerular filtration of liver-derived Agt (angiotensinogen) and the generation of intrarenal Ang II (angiotensin II) and that the filtered Agt is reabsorbed by proximal tubules in a manner dependent on megalin. In the present study, we aimed to study the role of megalin in the generation of renal Ang II and sodium handling during nephrotic syndrome. We generated proximal tubule-specific megalin KO (knockout) mice and crossed these animals with NEP25 mice, in which podocyte-specific injury can be induced by injection of the immunotoxin LMB2. Without podocyte injury, renal Agt staining was markedly diminished and urinary Agt increased in KO mice. However, renal Ang II was similar between KO and control mice on average: 117 (95% CI, 101–134) versus 101 (95% CI, 68–133) fmol/g tissue. We next tested the effect of megalin KO on intrarenal Ang II generation with podocyte injury. Control NEP25 mice showed markedly increased renal Agt staining and renal Ang II levels: 450 (336–565) fmol/g tissue. Megalin KO/NEP25 mice showed markedly diminished Agt reabsorption and attenuated renal Ang II: 199 (156–242) fmol/g tissue ( P <0.001). Compared with control NEP25 mice, megalin KO/NEP25 mice excreted 5-fold more sodium in the urine. Western blot analysis showed that megalin KO decreased NHE3 and the cleaved α and γ forms of Epithelial Na Channel. These data indicate that Agt reabsorbed by proximal tubules via megalin in nephrotic syndrome is converted to Ang II, which may contribute to sodium retention and edema formation by activating NHE3 and Epithelial Na Channel.

2018-07-01·Molecular cancer therapeutics2区 · 医学

Improving the In Vivo Efficacy of an Anti-Tac (CD25) Immunotoxin by Pseudomonas Exotoxin A Domain II Engineering

2区 · 医学

Article

作者: Jang, Youjin ; Pastan, Ira ; Lee, Fred ; Kaplan, Gilad ; Mazor, Ronit ; Leshem, Yasmin

Abstract:

Tac (CD25) is expressed on multiple hematologic malignancies and is a target for cancer therapies. LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38-kDa fragment of Pseudomonas exotoxin A (PE38). Although LMB-2 has shown high cytotoxicity toward Tac-expressing cancer cells in clinical trials, its efficacy was hampered by the formation of anti-drug antibodies against the immunogenic bacterial toxin and by dose-limiting off-target toxicity. To reduce toxin immunogenicity and nonspecific toxicity, we introduced six point mutations into domain III that were previously shown to reduce T-cell immunogenicity and deleted domain II from the toxin, leaving only the 11aa furin cleavage site, which is required for cytotoxic activity. Although this strategy has been successfully implemented for mesothelin and CD22-targeting immunotoxins, we found that removal of domain II significantly lowered the cytotoxic activity of anti-Tac immunotoxins. To restore cytotoxic activity in the absence of PE domain II, we implemented a combined rational design and screening approach to isolate highly active domain II–deleted toxin variants. The domain II–deleted variant with the highest activity contained an engineered disulfide-bridged furin cleavage site designed to mimic its native conformation within domain II. We found that this approach restored 5-fold of the cytotoxic activity and dramatically improved the MTD. Both of these improvements led to significantly increased antitumor efficacy in vivo. We conclude that the next-generation anti-Tac immunotoxin is an improved candidate for targeting Tac-expressing malignancies. Mol Cancer Ther; 17(7); 1486–93. ©2018 AACR.

100 项与 LMB-2 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
成人T细胞白血病/淋巴瘤	临床2期	美国	National Cancer Institute	2008-10-31
毛细胞白血病	临床2期	美国	National Cancer Institute	2006-05-02
皮肤黑色素瘤	临床2期	美国	National Institutes of Health Clinical Center	2005-12-01
转移性黑色素瘤	临床2期	美国	National Institutes of Health Clinical Center	2005-12-01
乳头状瘤	临床2期	美国	National Institutes of Health Clinical Center	2005-12-01
皮肤T细胞淋巴瘤	临床2期	美国	National Cancer Institute	2004-04-30
CD25阳性B细胞慢性淋巴细胞白血病	临床2期	美国	National Cancer Institute	2004-02-29
急性淋巴细胞白血病	临床1期	美国	National Cancer Institute	2004-04-01

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临床结果

适应症

分期

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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


NCT00321555 (CTgov)	临床2期	毛细胞白血病	15	Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin	壓獵範鬱鑰齋壓鬱顧鹹 = 構艱鬱鬱壓齋窪艱範製壓構壓膚鹹鏇壓餘襯蓋 (憲繭顧繭蓋衊選願襯醖, 遞網鑰壓壓網積餘襯顧 ~ 範範蓋構網顧夢繭鹽艱) 更多	-	2019-04-05
NCT00924170 (CTgov)	临床1/2期	成人T细胞白血病/淋巴瘤	18	LMB-2 (Leukemic Patients Receiving LMB-2 & At Least 25+250 mg/m^2 FC)	壓範衊夢範壓廠廠衊餘 = 蓋繭餘襯鹹鏇淵選鬱憲簾鏇窪夢顧壓構獵壓範 (夢壓選獵壓鏇鹽簾繭網, 遞糧襯觸簾鑰齋鏇繭廠 ~ 築壓壓鹽憲築範製選鏇) 更多	-	2017-09-08
NCT00924170 (CTgov)	临床1/2期	成人T细胞白血病/淋巴瘤	18	fludarabine cyclophosphamide (FC)+LMB-2 (All Other Patients)	壓範衊夢範壓廠廠衊餘 = 顧憲齋齋鏇憲壓製淵製簾鏇窪夢顧壓構獵壓範 (夢壓選獵壓鏇鹽簾繭網, 蓋糧範鏇餘獵齋蓋簾淵 ~ 願艱齋製齋獵觸鬱選範) 更多	-	2017-09-08
NCT00077922 (CTgov)	临床2期	CD25阳性B细胞慢性淋巴细胞白血病	15	LMB-2	積艱餘廠築鹹鏇廠衊壓 = 廠遞壓簾遞繭餘廠積構鹹顧齋憲網繭積鹹夢壓 (艱願鏇艱餘願淵獵顧鬱, 鑰膚衊廠簾選醖製廠鏇 ~ 範齋蓋襯壓顧觸壓願壓) 更多	-	2012-11-15
NCT00080535 (CTgov)	临床2期	皮肤T细胞淋巴瘤	10	LMB-2	艱壓餘範淵衊獵艱構淵 = 範壓網窪繭獵鬱蓋齋衊鬱遞衊襯顧網餘憲鹽醖 (積簾淵網餘鬱顧顧夢鑰, 鏇製築鹽壓糧網選網窪 ~ 醖餘選鬱鑰網構夢鏇積) 更多	-	2012-10-24