Delving into the Latest Updates on GTB-1550 with Synapse

Overview

Basic Info

Drug Type

Antibody toxin conjugate

Synonyms

Anti-CD19-anti-CD22-diphtheria-toxin-fusion-protein

+ [6]

Target

CD19 x CD22

Action

modulators, inhibitors

Mechanism

CD19 modulators(B-lymphocyte antigen CD19 modulators), CD22 inhibitors(CD22 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

B-Cell LeukemiaB-cell lymphoma recurrentB-cell lymphoma refractory

Originator Organization

University of Minnesota Masonic Cancer Center

Active Organization-

Inactive Organization

University of Minnesota Masonic Cancer Center

License Organization

GT Biopharma, Inc.

University of Minnesota

Drug Highest PhasePendingPhase 1/2

First Approval Date-

Regulation-

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Structure/Sequence

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This is a phase I/II study of DT2219 for the treatment of relapsed or refractory CD19 (+) and/or CD 22 (+) B-lineage leukemia and lymphoma. The study consists of two phases - a phase I dose/schedule finding component using the maximum tolerated dose identified during the previous phase I study, but with a higher number of doses and a two-stage phase II extension component to confirm safety and make a preliminary determination of the activity level by disease using the dose identified in phase I.

Start Date21 Dec 2015

Sponsor / Collaborator

University of Minnesota Masonic Cancer Center

NCT00889408

/ CompletedPhase 1IIT

A Phase I Study of DT2219ARL, A Bispecific Singe Chain Immunotoxin for the Treatment of Relapsed or Refractory CD19(+), CD22(+) B-Lineage Leukemia or Lymphoma

This is a phase I dose escalation study of DT2219ARL for the treatment of relapsed or refractory B-lineage leukemia and lymphoma. Patients will receive a single course of DT2219ARL as a 4 hour infusion on days 1, 3, 5, and 8. Weekly follow-up will continue through day 29, at which time a disease reassessment will be done. For patients in remission, follow-up will continue monthly until disease progression or start of a new treatment. Otherwise day 29 will be the final study visit if there is no ongoing toxicity.
This phase I study will use Continual Reassessment Method (CRM) to establish a maximum tolerated dose (MTD) of DT2219ARL. Up to 3 dose levels will be tested with an additional dose level (-1) if dose level 1 proves too toxic. The goal of CRM is to identify the dose level which correspondences to a desired toxicity rate of 33% or less using grade 3 or 4 capillary leak syndrome and any grade 3 or greater toxicity attributed to DT2219ARL as the targeted toxicity (based on CTCAE version 4).

Start Date02 Dec 2013

Sponsor / Collaborator

University of Minnesota Masonic Cancer Center

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100 Clinical Results associated with GTB-1550

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100 Translational Medicine associated with GTB-1550

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100 Patents (Medical) associated with GTB-1550

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4

Literatures (Medical) associated with GTB-1550

15 Mar 2015·Clinical Cancer ResearchQ1 · MEDICINE

Phase I Study of a Bispecific Ligand-Directed Toxin Targeting CD22 and CD19 (DT2219) for Refractory B-cell Malignancies

Q1 · MEDICINE

Article

Author: Kantarjian, Hagop ; McClune, Brian ; Warlick, Erica D. ; Grzywacz, Bartosz ; Verneris, Michael R. ; Frankel, Arthur E. ; Lazaryan, Aleksandr ; Weisdorf, Daniel J. ; Vallera, Daniel A. ; Cao, Qing ; Lewis, Dixie ; Bachanova, Veronika ; Ustun, Celalettin ; Miller, Jeffrey S.

AbstractPurpose: The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase I dose-escalation study to assess the safety, maximum tolerated dose, and preliminary efficacy of DT2219 in patients with relapsed/refractory B-cell lymphoma or leukemia.Experimental Design: DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose-limiting toxicity (DLT) was observed.Results: Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events, including weight gain, low albumin, transaminitis, and fever were transient grade 1–2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizing antibody (30%).Conclusions: We have determined the safety of a novel immunotoxin DT2219 and established its biologically active dose between 40 and 80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned. Clin Cancer Res; 21(6); 1267–72. ©2015 AACR.

01 Sep 2009·Leukemia ResearchQ4 · MEDICINE

Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy

Q4 · MEDICINE

Article

Author: Angela Panoskaltsis-Mortari ; Elizabeth P. Taras ; Andrew R. Sicheneder ; Hua Chen ; Daniel A. Vallera

A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two scFv ligands recognizing CD19 and CD22 and catalytic DT390 was genetically enhanced for superior in vivo anti-leukemia activity. Genetic alterations included reverse orienting VH-VL domains and adding aggregation reducing/stabilizing linkers. In vivo, these improvements resulted in previously unseen long-term tumor-free survivors measured in a bioluminescent xenograft imaging model in which the progression of human Raji Burkitt's lymphoma could be tracked in real time and in a Daudi model as well. Studies showed DT2219ARL was potent (IC50s 0.06-0.2 nM range) and selectively blockable. Imaging studies indicated the highly invasive nature of this B cell malignancy model and showed it likely induced pre-terminal hind limb paralysis because of metastasis to spinal regions prevented by DT2219ARL. DT2219ARL represents a new class of bispecific biological that can be continually improved by genetic mutation.

15 May 2005·Clinical Cancer ResearchQ1 · MEDICINE

A Bispecific Recombinant Immunotoxin, DT2219, Targeting Human CD19 and CD22 Receptors in a Mouse Xenograft Model of B-Cell Leukemia/Lymphoma

Q1 · MEDICINE

Article

Author: Kuroki, David W. ; Vallera, Daniel A. ; Chen, Hua ; Shu, Yanqun ; Todhunter, Deborah A. ; Sicheneder, Andy

AbstractA novel bispecific single-chain fusion protein, DT2219, was assembled consisting of the catalytic and translocation domains of diphtheria toxin (DT390) fused to two repeating sFv subunits recognizing CD19 and CD22 and expressed in Escherichia coli. Problems with yield, purity, and aggregation in the refolding step were solved by incorporating a segment of human muscle aldolase and by using a sodium N-lauroyl-sarcosine detergent-based refolding procedure. Problems with reduced efficacy were addressed by combining the anti-CD19 and anti-CD22 on the same single-chain molecule. DT2219 had greater anticancer activity than monomeric or bivalent immunotoxins made with anti-CD19 and anti-CD22 sFv alone and it showed a higher level of binding to patient leukemia cells and to CD19+CD22+ Daudi or Raji cells than did anti-CD19 and anti-CD22 parental monoclonal antibodies. The resulting DT2219, mutated to enhance its avidity, was cytotoxic to Daudi cells in vitro (IC50 = 0.3 nmol/L). In vivo, DT2219 was effective in a flank tumor therapy model in which it significantly inhibited tumor growth (P < 0.05) and in a systemic model in which it significantly prolonged survival of severe combined immunodeficient mice with established Daudi (P < 0.008) compared with controls. DT2219 has broader reactivity in recognizing B-cell malignancies, has more killing power, and requires less toxin than using individual immunotoxin, which warrants further investigation as a new drug for treating B leukemia/lymphoma.

100 Deals associated with GTB-1550

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Leukemia	Phase 2	United States	University of Minnesota Masonic Cancer Center	21 Dec 2015
B-cell lymphoma recurrent	Phase 2	United States	University of Minnesota Masonic Cancer Center	21 Dec 2015
B-cell lymphoma refractory	Phase 2	United States	University of Minnesota Masonic Cancer Center	21 Dec 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02370160 (CTgov)	Phase 1/2	B-Cell Leukemia \| B-cell lymphoma refractory \| B-cell lymphoma recurrent	18	DT2219ARL	andblbyveu(imhiecqjyo) = cxugotlyhe recxbvjgrh (sbkjzyaqxm, wgcnnvoesq - utpcckbien) View more	-	13 Jan 2020
NCT00889408 (Pubmed \| Clin Cancer Res) Manual	Phase 1	Chronic Lymphocytic Leukemia	25	DT2219	(gibpruzeys) = including weight gain, low albumin, transaminitis, and fever were transient grade 1-2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day) tdbgjzxbry (hfasknesmq ) View more	Positive	15 Mar 2015

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Deal

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Clinical Trial

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Approval

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Biosimilar

Competitive landscape of biosimilars in different countries/locations. Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3.

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