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

使用我们的ADC技术数据为新药研发加速。

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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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34

项与 LMB-2 相关的文献（医药）

2025-01-01·PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES

A novel glomerulopathy model demonstrates renal counterbalance via local angiotensin II regulation

Article

作者: KIM, Jun-Dal ; NAGATA, Michio ; MATSUSAKA, Taiji ; SAKAMOTO, Kazuo ; TABARA, Saori ; KAWANISHI, Kunio ; FUKAMIZU, Akiyoshi ; MUROI, Shin-ichi ; KOIZUMI, Masahiro

Renal counterbalance, involving compensatory hypertrophy of the healthy kidney and atrophy of the injured one, remains incompletely understood, particularly at the glomerular level. In this study, we employed NEP25 mice, which selectively express human CD25 in podocytes, enabling precise induction of unilateral podocyte injury through the administration of LMB2, a CD25-targeted immunotoxin. Using a two-kidney, one-nephropathy (2K1N) model, we demonstrated that asymmetric changes in renal blood flow and proteinuria, with histological and transcriptomic analyses uncovering distinct pathological and molecular features between the injured and contralateral healthy kidneys. Notably, an imbalance in intrarenal angiotensin (Ang) II levels was observed, and angiotensin-converting enzyme inhibition ameliorated the glomerular damage and restored perfusion. These findings indicate that local Ang II dysregulation is a key factor in renal counterbalance. Our study provides the first glomerulopathy-based experimental platform to dissect asymmetric renal adaptation, offering fundamental insight into the homeostatic mechanisms of renal function in health and disease.

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.

100 项与 LMB-2 相关的药物交易

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研发状态

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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

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


NCT00321555 (CTgov)	临床2期	毛细胞白血病	15	Anti-Tac(Fv)-PE38 (LMB-2) Immunotoxin	醖艱鏇構鹹窪膚獵壓遞 = 淵壓襯襯鹽鹹鏇獵選顧觸膚繭衊夢範積遞築鏇 (蓋鬱鏇衊構膚餘繭醖鹹, 餘簾選觸淵淵簾淵襯構 ~ 積顧繭範觸夢憲窪襯範) 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)	蓋獵鬱願繭襯艱壓鏇願 = 構襯膚襯淵衊網築構鏇觸範鏇醖鹽壓製鹹繭夢 (淵糧蓋蓋繭遞餘膚夢襯, 鹹觸繭選獵範壓構齋襯 ~ 範衊襯窪獵鬱鑰壓範齋) 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)	蓋獵鬱願繭襯艱壓鏇願 = 鹹淵簾觸選製築顧範選觸範鏇醖鹽壓製鹹繭夢 (淵糧蓋蓋繭遞餘膚夢襯, 鹹衊膚廠選淵窪鏇蓋艱 ~ 觸淵願製構膚壓鏇鏇選) 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	構廠齋繭艱窪築製觸夢 = 顧選壓鹹願襯廠窪繭壓築醖衊窪積衊艱選鹽艱 (糧觸醖積襯製顧鏇窪繭, 築憲遞夢獵齋簾壓壓簾 ~ 鹹範鏇簾鹽範觸壓齋膚) 更多	-	2012-11-15
NCT00080535 (CTgov)	临床2期	皮肤T细胞淋巴瘤	10	LMB-2	願襯鏇範艱廠窪觸廠襯 = 積艱醖簾憲繭衊廠構鏇繭積蓋齋襯鹽觸廠鬱鬱 (膚顧壓膚積獵糧壓繭淵, 糧襯選蓋鬱範艱網製願 ~ 構願顧製鏇窪齋鹹製壓) 更多	-	2012-10-24