Delving into the Latest Updates on D2C7-based immunotoxins(Istari Oncology, Inc.) with Synapse

Overview

Basic Info

Drug Type

Antibody toxin conjugate

Synonyms

D2C7-Immunotoxin

+ [3]

Target

EGFR

Mechanism

EGFR antagonists(Epidermal growth factor receptor erbB1 antagonists)

Therapeutic Areas

NeoplasmsNervous System DiseasesOther Diseases

Active Indication

Glioblastoma MultiformeGlioblastoma, IDH-WildtypeRecurrent Glioblastoma+ [2]

Inactive Indication-

Originator Organization

Istari Oncology, Inc.Startup

Active Organization

Duke University

Genentech, Inc.

Istari Oncology, Inc.Startup

Inactive Organization-

Drug Highest PhasePhase 1/2

First Approval Date-

Regulation-

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Structure

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Gene Sequence

Sequence Code 19691121H

Sequence Code 19691123L

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.

Start Date01 Nov 2024

Sponsor / Collaborator

Duke University

[+1]

NCT05734560 / RecruitingPhase 1/2IIT

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).

Start Date06 Sep 2023

Sponsor / Collaborator

Duke University

[+1]

NCT04547777 / RecruitingPhase 1IIT

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.

Start Date09 Jul 2021

Sponsor / Collaborator

Duke University

[+1]

100 Clinical Results associated with D2C7-based immunotoxins(Istari Oncology, Inc.)

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100 Translational Medicine associated with D2C7-based immunotoxins(Istari Oncology, Inc.)

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100 Patents (Medical) associated with D2C7-based immunotoxins(Istari Oncology, Inc.)

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7

Literatures (Medical) associated with D2C7-based immunotoxins(Istari Oncology, Inc.)

08 Feb 2023·Science Translational MedicineQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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. ; Osorio, Cristina ; McDowall, Charlotte ; Duncker, Patrick C. ; Ashley, David M. ; Pastan, Ira H. ; Enterline, David S. ; Chandramohan, Vidyalakshmi ; Gunn, Michael Dee ; 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.

01 Dec 2019·Journal for ImmunoTherapy of CancerQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: Healy, Patrick ; Pastan, Ira H ; Bigner, Darell D ; Yu, Yen-Rei ; Nair, Smita K ; Yu, Xin ; Bao, Xuhui ; McDowall, Charlotte ; Parker, Scott ; 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.

01 Apr 2017·Applied Microbiology and BiotechnologyQ3 · ENGINEERING & TECHNOLOGY

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

Q3 · ENGINEERING & TECHNOLOGY

Article

Author: 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 Deals associated with D2C7-based immunotoxins(Istari Oncology, Inc.)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glioblastoma Multiforme	Phase 2	US	Duke University	06 Sep 2023
Glioblastoma, IDH-Wildtype	Phase 1	US	Duke University	01 Nov 2024
Recurrent Glioblastoma	Phase 1	US	Duke University	01 Nov 2024
Malignant glioma of brain	Phase 1	US	Duke University	09 Jul 2021
Recurrent Malignant Glioma	Phase 1	US	Duke University	05 May 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04547777 (ASCO2022) Manual	Phase 1	Recurrent Malignant Glioma	8	D2C7-it+2141-V11	(gdxfcbyiyr) = iamckksfik cblmuxtgwo (hqfkicuzjd )	Positive	02 Jun 2022
NCT02303678 (ASCO2020) Manual	Phase 1	Recurrent Malignant Glioma	43	D2C7 immunotoxin	(zzvvoehtfo) = 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 exgzvawpva (ddiywwdtqy ) View more	Positive	29 May 2020
NCT02303678 (Pubmed \| Appl Microbiol Biotechnol)	Phase 1/2	Malignant glioma of brain \| Recurrent Malignant Glioma	81	D2C7-(scdsFv)-PE38KDEL	xddzdvllqs(qkymxixmvc) = cjjpymfbge oabytwwvpn (lsdmqpxsli, ± 0.1)	-	01 Apr 2017