D2C7-based immunotoxins(Istari Oncology, Inc.)(D2C7-based immunotoxins(Istari Oncology, Inc.)) - 药物靶点：EGFR_在研适应症：多形性胶质母细胞瘤，胶质母细胞瘤，IDH野生型，复发性胶质母细胞瘤_专利_临床

概要

基本信息

药物类型

抗体偶联毒素

别名

D2C7-Immunotoxin

+ [3]

靶点

EGFR

作用机制

EGFR拮抗剂(表皮生长因子受体erbB1拮抗剂)

治疗领域

肿瘤神经系统疾病其他疾病

在研适应症

多形性胶质母细胞瘤胶质母细胞瘤，IDH野生型复发性胶质母细胞瘤+ [2]

非在研适应症-

原研机构

Istari Oncology, Inc.初创企业

在研机构

Duke University

Genentech, Inc.

Istari Oncology, Inc.初创企业

非在研机构-

最高研发阶段临床1/2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

使用我们的ADC技术数据为新药研发加速。

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序列信息

Sequence Code 19691121H

Sequence Code 19691123L

关联

5

项与 D2C7-based immunotoxins(Istari Oncology, Inc.) 相关的临床试验

NCT06455605 / Not yet recruiting临床1期IIT

Clinical Trial of D2C7-IT + 2141-V11 Combination Immunotherapy Administered Via Convection Enhanced Delivery in Non-enhancing Tumor Post-resection of Recurrent Glioblastoma, Followed by Cervical Perilymphatic Subcutaneous Injections of 2141-V11

The purpose of this study is to assess the safety and efficacy of the combination of D2C7-IT+2141-V11 administered in the non-enhancing tumor of patients with resected recurrent glioblastoma (rGBM) via convection enhanced delivery (CED), followed by subcutaneous cervical perilymphatic injections (CPLIs) of 2141-V11 2 and 4 weeks post infusion, then every 3 weeks for a year, and every 4-6 weeks thereafter if patients benefit from therapy.

开始日期2024-11-01

申办/合作机构

Duke University

[+1]

NCT05734560 / Recruiting临床1/2期IIT

Delivery of D2C7-IT and 2141-V11 Combination Immunotherapy in Residual Disease for Adult Patients With Newly Diagnosed MGMT Unmethylated Glioblastoma and Perilymphatic Subcutaneous Injections of 2141-V11

The purpose of this research study is to determine the safety and efficacy of administering a single intracerebral (within the brain) dose of investigational compounds called D2C7-immunotoxin (IT) and 2141-V11 in residual disease (within tumor margins) after surgery, followed by later repeated injections of 2141-V11 in the subcutaneous area (under the skin) around the lymph nodes of the head and neck for adults newly diagnosed with a type of cancerous brain tumor called glioblastoma. The word "investigational" means the study drugs are still being tested in research studies and are not approved by the U.S. Food and Drug Administration (FDA).

开始日期2023-09-06

申办/合作机构

Duke University

[+1]

NCT04547777 / Recruiting临床1期IIT

A Phase 1 Trial of D2C7-IT in Combination With an Fc-engineered Anti-CD40 Monoclonal Antibody (2141-V11) Administered Intratumorally Via Convection-Enhanced Delivery for Adult Patients With Recurrent Malignant Glioma

This is a phase 1 study of an anti-CD40 monoclonal antibody (2141-V11) in combination with D2C7-IT for patients with recurrent World Health Organization (WHO) grade III or IV malignant glioma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.

开始日期2021-07-09

申办/合作机构

Duke University

[+1]

100 项与 D2C7-based immunotoxins(Istari Oncology, Inc.) 相关的临床结果

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100 项与 D2C7-based immunotoxins(Istari Oncology, Inc.) 相关的转化医学

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100 项与 D2C7-based immunotoxins(Istari Oncology, Inc.) 相关的专利（医药）

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7

项与 D2C7-based immunotoxins(Istari Oncology, Inc.) 相关的文献（医药）

2023-02-08·Science Translational Medicine1区 · 医学

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models

1区 · 医学

Article

作者: Herndon, James E. ; Briley, Aaron ; Parker, Scott ; Sanchez-Perez, Luis ; Bigner, Darell D. ; Swartz, Adam M. ; Nair, Smita K. ; Tedder, Thomas F. ; Desjardins, Annick ; Knorr, David A. ; McDowall, Charlotte ; Osorio, Cristina ; Duncker, Patrick C. ; Ashley, David M. ; Pastan, Ira H. ; Enterline, David S. ; Gunn, Michael Dee ; Chandramohan, Vidyalakshmi ; Yu, Yen-Rei A. ; McLendon, Roger E.

D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8 + T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6 + CD8 + T cells with a progenitor phenotype and decreased terminally exhausted CD8 + T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8 + T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.

2019-12-01·Journal for ImmunoTherapy of Cancer2区 · 医学

Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations

2区 · 医学

ArticleOA

作者: Healy, Patrick ; Pastan, Ira H ; Bigner, Darell D ; Yu, Yen-Rei ; Nair, Smita K ; Yu, Xin ; Bao, Xuhui ; Parker, Scott ; McDowall, Charlotte ; Chandramohan, Vidyalakshmi ; Desjardins, Annick ; Gunn, Michael D ; Gromeier, Matthias

BACKGROUNDD2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma.METHODSTo study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test.RESULTSD2C7-IT effectively killed CT-2A-dmEGFRvIII (IC₅₀ = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC₅₀ = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge.CONCLUSIONSThese data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.

2017-04-01·Applied Microbiology and Biotechnology3区 · 工程技术

Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial

3区 · 工程技术

Article

作者: Kuan, Chien-Tsun ; Pegram, Charles N ; Piao, Hailan ; Bigner, Darell D ; Chandramohan, Vidyalakshmi ; Pastan, Ira H ; Szafranski, Scott E

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel recombinant Pseudomonas exotoxin A-based immunotoxin (IT), targeting both wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins overexpressed in glioblastomas. Initial pre-clinical testing demonstrated the anti-tumor efficacy of D2C7-IT against orthotopic glioblastoma xenograft models expressing EGFRwt, EGFRvIII, or both EGFRwt and EGFRvIII. A good laboratory practice (GLP) manufacturing process was developed to produce sufficient material for a phase I/II clinical trial. D2C7-IT was expressed under the control of the T7 promoter in Escherichia coli BLR (λ DE3). D2C7-IT was produced by a 10-L batch fermentation process and was then purified from inclusion bodies using anion exchange, size exclusion, and an endotoxin removal process that achieved a yield of over 300 mg of purified protein. The final vialed batch of D2C7-IT for clinical testing was at a concentration of 0.12 ± 0.1 mg/mL, the pH was at 7.4 ± 0.4, and endotoxin levels were below the detection limit of 10 EU/mL (1.26 EU/mL). The stability of the vialed D2C7-IT has been monitored over a period of 42 months through protein concentration, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing, size exclusion chromatography, cytotoxicity, sterility, and pH measurements. The vialed D2C7-IT is currently being tested in a phase I/II clinical trial by intratumoral convection-enhanced delivery for 72 h in patients with recurrent glioblastoma (NCT02303678, D2C7 for Adult Patients with Recurrent Malignant Glioma; clinicaltrials.gov ).

100 项与 D2C7-based immunotoxins(Istari Oncology, Inc.) 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
多形性胶质母细胞瘤	临床2期	美国	Duke University	2023-09-06
胶质母细胞瘤，IDH野生型	临床1期	美国	Duke University	2024-11-01
复发性胶质母细胞瘤	临床1期	美国	Duke University	2024-11-01
脑恶性胶质瘤	临床1期	美国	Duke University	2021-07-09
复发性恶性胶质瘤	临床1期	美国	Duke University	2015-05-05

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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


NCT04547777 (ASCO2022) 人工标引	临床1期	复发性恶性胶质瘤	8	D2C7-it+2141-V11	(積憲製夢鏇衊範願鹹齋) = 遞構壓憲夢鹽構願淵鬱繭膚艱淵鏇鏇憲遞蓋壓 (觸積鏇鹽憲遞膚壓鹽觸 )	积极	2022-06-02
NCT02303678 (ASCO2020) 人工标引	临床1期	复发性恶性胶质瘤	43	D2C7 immunotoxin	(網製襯願願範觸艱鏇積) = grade 4 seizure (n=1) on DL3, grade 3 confusion and pyramidal tract syndrome (n=1) on DL13, and grade 4 cerebral edema (n=1) and grade 3 dysphasia (n=1) on DL17 鹽蓋遞網襯網範築憲積 (獵襯網選蓋願廠範鹹糧 ) 更多	积极	2020-05-29
NCT02303678 (Pubmed \| Appl Microbiol Biotechnol)	临床1/2期	脑恶性胶质瘤 \| 复发性恶性胶质瘤	81	D2C7-(scdsFv)-PE38KDEL	鏇鬱淵壓築膚艱糧鑰繭(遞壓糧製夢襯鹽餘蓋憲) = 壓淵構簾蓋餘鬱範鏇築襯願憲鬱膚觸鏇鹹顧製 (襯蓋壓餘衊積觸衊選醖, ± 0.1)	-	2017-04-01