Toxicology and pharmacokinetics of DT388IL3, a fusion toxin consisting of a truncated diphtheria toxin (DT388) linked to human interleukin 3 (IL3), in cynomolgus monkeys.

Abstract:

:The fusion toxin DT388IL3 composed of the catalytic and translocation domains of diphtheria toxin (DT388) linked to interleukin-3 (IL3) was administered to 6 cynomolgus monkeys which possessed cross-reactive IL3 receptors. Groups of 2 animals (1 male and 1 female) received up to 6 every other day slow intravenous infusions of 40, 60, or 100 microg/kg DT388IL3. Monkeys given 40 or 60 microg/kg showed mild or moderate transient malaise and anorexia, respectively, without evidence of organ damage by blood tests or histopathology. Animals treated at 100 microg/kg showed severe malaise and anorexia. The female monkey had moderate to severe vasculitis in multiple tissues. Necropsies were performed on the 40 microg/kg monkeys on day 14 and the 100 microg/kg monkeys on days 6 and 7. DT388IL3 plasma half-life was approximately 30 min with a peak concentration of 0.45 microg/ml or 10,000 pM (IC50 for AML blasts treated in vitro was 6 pM). Immune responses were minimal in 4 animals tested at 12 days and 2 animals tested at 30 days post treatment with anti-DT388IL3 levels < 1 microg/ml. Bone marrow aspirates were obtained on all animals at day 19 or at necropsy and revealed myeloid suppression in the females and myeloid hyperplasia in the males irrespective of dose groups. The maximal tolerated dose of 60 microg/kg for 6 doses is markedly higher than other recombinant diphtheria toxins and provides a dose level sufficient for anti-leukemic activity in vitro and in rodent models. Thus, we propose this agent is a promising drug for AML patients.

journal_name

Leuk Lymphoma

journal_title

Leukemia & lymphoma

authors

Cohen KA,Liu TF,Cline JM,Wagner JD,Hall PD,Frankel AE

doi

10.1080/10428190410001663572

keywords:

subject

Has Abstract

pub_date

2004-08-01 00:00:00

pages

1647-56

issue

8

eissn

1042-8194

issn

1029-2403

pii

HXENEU9HE0QKMV92

journal_volume

45

pub_type

杂志文章
  • Phase I/II study of pixantrone in combination with cyclophosphamide, vincristine, and prednisone in patients with relapsed aggressive non-Hodgkin lymphoma.

    abstract::Pixantrone is a potentially more effective, less cardiotoxic alternative to doxorubicin for patients with aggressive non-Hodgkin lymphoma (aNHL). This phase I/II non-comparative study evaluated pixantrone in place of doxorubicin in the standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone),...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428194.2010.546016

    authors: Borchmann P,Herbrecht R,Wilhelm M,Morschhauser F,Hess G,Cernohous P,Veals SA,Singer JW,Engert A

    更新日期:2011-04-01 00:00:00

  • Enzymatic activities of circulating plasma proteasomes in newly diagnosed multiple myeloma patients treated with carfilzomib, lenalidomide and dexamethasone.

    abstract::The proteasome inhibitor carfilzomib is highly effective in the treatment of multiple myeloma. It irreversibly binds the chymotrypsin-like active site in the β5 subunit of the 20S proteasome. Despite impressive response rates when carfilzomib is used in combination with immunomodulatory agents in newly diagnosed multi...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/10428194.2016.1214953

    authors: Manasanch EE,de Larrea CF,Zingone A,Steinberg SM,Kwok M,Tageja N,Bhutani M,Kazandjian D,Roschewski M,Wu P,Carter G,Zuchlinski D,Mulquin M,Lamping L,Costello R,Burton D,Gil LA,Figg WD,Maric I,Calvo KR,Yuan C,Stet

    更新日期:2017-03-01 00:00:00

  • Peripheral blood progenitor cell harvesting in multiple myeloma and malignant lymphoma.

    abstract::Peripheral blood progenitor cells are being used increasingly as part of the treatment protocol for a variety of haematological malignancies. The most appropriate mobilisation therapy and the optimum collection procedures have yet to be fully elucidated. 28 patients with myeloma (9), NHL (11) and HD (8) underwent PBSC...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199509112208

    authors: Scott MA,Ager S,Apperley JF,Jestice HK,Bloxham DM,Boraks P,Mahendra P,Marcus RE

    更新日期:1995-11-01 00:00:00

  • Coexistent multiple myeloma and myelofibrosis.

    abstract::Although the association of bone marrow fibrosis with plasma cell dyscrasias has already been described in several reports, the close relationship between these entities still remains unclear. In this report we describe a patient with clinical and pathologic findings which initially suggested a diagnosis of myelofibro...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199309148567

    authors: Pulsoni A,Bianco P,La Verde G,Mecarocci S,Petrucci MT,Torromeo C,Avvisati G

    更新日期:1993-07-01 00:00:00

  • Establishment and characterization of a new Ph1-positive ALL cell line (ALL/MIK) presenting bcr gene rearrangement on bcr-2 and ALL-type bcr/abl transcript: suggestion of in vitro differentiation to monocytoid lineage.

    abstract::A new Ph1-positive acute lymphoblastic leukemia cell line, designated as ALL/MIK, has been developed from a patient with Ph1-positive acute leukemia. The ALL/MIK cells showed an immunophenotype of common ALL with rearranged JH and Jk genes. The ALL/MIK cells showed no M-bcr rearrangement using Southern blot analysis w...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199409059601

    authors: Higa T,Okabe M,Kunieda Y,Kodama S,Itaya T,Kurosawa M,Sakurada K,Maekawa I,Shoji M,Kasai M

    更新日期:1994-01-01 00:00:00

  • Chemotherapy-related changes in central nervous system phospholipids and neurocognitive function in childhood acute lymphoblastic leukemia.

    abstract::Long-term survivors of childhood leukemia are at risk for neurocognitive impairment, although the neurophysiological basis is not well understood. The purpose of this study was to explore associations between changes in cerebrospinal fluid (CSF) phospholipids and neurocognitive function in children undergoing chemothe...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428194.2012.717080

    authors: Krull KR,Hockenberry MJ,Miketova P,Carey M,Moore IM

    更新日期:2013-03-01 00:00:00

  • Primary immunodeficiencies and lymphoma: a systematic review of literature.

    abstract::The management of lymphoma in patients with primary immunodeficiency (PID) is challenging because of its poor prognosis and complex therapeutic approaches. We conducted a systematic literature review of case-reports, case-series, and cohorts indexed in MEDLINE reporting the association of lymphoma and PID. One hundred...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/10428194.2019.1672056

    authors: Herber M,Mertz P,Dieudonné Y,Guffroy B,Jung S,Gies V,Korganow AS,Guffroy A

    更新日期:2020-02-01 00:00:00

  • Herbs in hemato-oncological care: an evidence-based review of data on efficacy, safety, and drug interactions.

    abstract::Herbal remedies are clearly a complementary and alternative modality used frequently by patients with hemato-oncological neoplasias during the course of their specific treatment. This review focuses on the potential safety and efficacy of herbs which are either used often or even on a daily basis by patients with hema...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.3109/10428194.2010.487622

    authors: Ben-Arye E,Attias S,Tadmor T,Schiff E

    更新日期:2010-08-01 00:00:00

  • The role of cyclic-AMP binding protein (CREB) in leukemia cell proliferation and acute leukemias.

    abstract::Leukemia is a result of accumulating genetic alterations. The collaboration of mutations that offer survival and proliferative signals, together with mutations that result in lack of differentiation, is thought to cause a leukemic phenotype. The cyclic-AMP Response Element Binding Protein (CREB) is a transcription fac...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.1080/1042819031000151095

    authors: Shankar DB,Sakamoto KM

    更新日期:2004-02-01 00:00:00

  • Angiogenic and lymphangiogenic molecules in hematological malignancies.

    abstract::In this review, the role of angiogenic and lymphangiogenic growth factors in hematological malignancies is summarized, alongside with possible therapeutic applications. Recent data demonstrate the importance of angiogenesis in hematologic malignancies including leukemia, lymphoma, and multiple myeloma. Expression of a...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.1080/10428190290005964

    authors: Orpana A,Salven P

    更新日期:2002-02-01 00:00:00

  • Augmentation of the activity of an immunotoxin, anti-Tac(Fv)-PE40KDEL, in T cell lines infected with human T cell leukemia virus type-I.

    abstract::Therapy with an immunotoxin, anti-Tac(Fv)-PE38, which is a conjugate of the variable domains of an anti-Tac monoclonal antibody and Pseudomonas exotoxin, was reported to be useful for adult T cell leukemia (ATL) patients but a considerable amount of the immunotoxin is needed for the therapy and some side effects were ...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/10428190290017042

    authors: Ohno N,Kreitman RJ,Saito T,Masamoto I,Uozumi K,Hanada S,Takeuchi S,Furukawa T,Sumizawa T,Arima T,Akiyama S

    更新日期:2002-04-01 00:00:00

  • The role of T cell costimulation by CD80 in the initiation and maintenance of the immune response to human leukemia.

    abstract::Most human myeloid leukemias express both class I and class II HLA and it has been postulated that leukemia-associated peptides are presented by those molecules. It is possible, however, that leukemia cells escape the immune surveillance by lacking expression of "costimulatory" molecules required for activating the im...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/10428199909169607

    authors: Matsumoto K,Anasetti C

    更新日期:1999-11-01 00:00:00

  • Low-dose fludarabine with or without darbepoetin alfa in patients with chronic lymphocytic leukemia and comorbidity: primary results of the CLL9 trial of the German CLL Study Group.

    abstract::This study was planned as a phase 3 trial to investigate low-dose fludarabine with or without darbepoetin alfa in older patients with previously untreated or treated chronic lymphocytic leukemia (CLL) and comorbidity. Due to slow recruitment, the study was terminated prematurely after accrual of 97 patients who, on av...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.3109/10428194.2015.1079314

    authors: Goede V,Busch R,Bahlo J,Chataline V,Kremers S,Müller L,Reschke D,Schlag R,Schmidt B,Vehling-Kaiser U,Wedding U,Stilgenbauer S,Hallek M

    更新日期:2016-01-01 00:00:00

  • The role of Aktand RAFTK in beta1 integrin mediated survival of precursor B-acute lymphoblastic leukemia cells.

    abstract::In this study, we report that the related adhesion focal tyrosine kinase RAFTK, is an upstream kinase in beta1 integrin mediated activation of Akt. Stimulation through beta1 integrins by fibronectin reversed apoptosis induced by adriamycin. Inhibitors of phosphatidylinositol 3-kinase (PI3 kinase)/Akt (LY 294002), tyro...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/1042819021000003009

    authors: Sarkar S,Svoboda M,de Beaumont R,Freedman AS

    更新日期:2002-08-01 00:00:00

  • Attempted reconstruction of the immune system using low doses of interleukin 2 in chronic lymphocytic leukemia patients treated with 2-chlorodeoxyadenosine: results of a pilot study.

    abstract::This study was designed to investigate the immunostimulatory effect of low dose Il-2 treatment in B-CLL patients previously treated with 2-chlorodeoxyadenosine (2CdA) in whom severe depletion of T lymphocyte subsets was observed. Four patients enrolled into the study had previously been treated with 3-6 courses of 2Cd...

    journal_title:Leukemia & lymphoma

    pub_type: 临床试验,杂志文章

    doi:10.3109/10428199909050958

    authors: Dmoszyńska A,Legiec W,Wach M

    更新日期:1999-07-01 00:00:00

  • Clinical significance of pre- and 1-year post-transplant serum ferritin among adult transplant recipients.

    abstract::To clarify the significance of post-transplant serum ferritin (SF), we retrospectively assessed pre- and post-transplant SF. Among 256 patients undergoing allogeneic stem cell transplant (SCT) for hematologic malignancies between 2000 and 2011, those who had relapsed within 1 year were excluded, and 110 patients survi...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428194.2013.842981

    authors: Tachibana T,Tanaka M,Numata A,Matsumoto K,Tomita N,Fujimaki K,Taguchi J,Sakai R,Fujita H,Fujisawa S,Maruta A,Ishigatsubo Y,Kanamori H

    更新日期:2014-06-01 00:00:00

  • Catalytic mammalian target of rapamycin inhibitors as antineoplastic agents.

    abstract::The mammalian target of rapamycin (mTOR) pathway is a major therapeutic target in the treatment of hematological malignancies, as it controls cellular events of high importance for regulation of mRNA translation and protein production. Rapalogs, or first-generation mTOR inhibitors, have produced only modest clinical b...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428194.2015.1026816

    authors: Mohindra NA,Platanias LC

    更新日期:2015-01-01 00:00:00

  • Two consecutive spontaneous regressions to chronic phase in a patient with blastic transformation of chronic myelogenous leukemia.

    abstract::In this report, we present a patient with chronic myeloid leukemia (CML) in blastic phase who had two consecutive episodes of spontaneous regression back to chronic phase without chemotherapy. Although, spontaneous remission (SR) is well documented in acute leukemia, SR in CML blastic phase is extremely rare and to th...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199809068579

    authors: Cağirgan S,Sencan M,Tombuloglu M,Ozdemir E,Hekimgil M,Büyükkeçeci F

    更新日期:1998-04-01 00:00:00

  • Dose reductions in ibrutinib therapy are not associated with inferior outcomes in patients with chronic lymphocytic leukemia (CLL).

    abstract::Ibrutinib is a first-in-class small molecule inhibitor that has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend lifelong administration at a fixed daily dose of 420 mg. Data from real-world studies indicate up to 17.5% of patients discontinue ibrutinib due to toxicity. Hypothetically, j...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/10428194.2018.1554862

    authors: Akhtar OS,Attwood K,Lund I,Hare R,Hernandez-Ilizaliturri FJ,Torka P

    更新日期:2019-07-01 00:00:00

  • Induction of differentiation of myeloid leukemic cells by busulphan: in vivo and in vitro observations.

    abstract::Treatment of a 74 year old patient with chronic myelogenous leukemia (CML) with busulphan resulted in an abrupt and pronounced decrease of the white blood cell (WBC) count with restoration of normal peripheral blood cell morphology and regression of splenomegaly. The Philadelphia positive (Ph+) clone was however still...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199309087006

    authors: Michaeli J,Fibach E,Rachmilewitz EA

    更新日期:1993-10-01 00:00:00

  • Familial erythroleukemia: a distinct clinical and genetic type of familial leukemias.

    abstract::A family with erythroleukemia is presented, in which father and son were diagnosed at the same age, but 20 years apart, with almost identical clinical and morphological features of the disease. No environmental factors were identified. The karyotypic abnormalities of the bone marrow blasts in the son demonstrated 2 ma...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.3109/10428199809057551

    authors: Novik Y,Marino P,Makower DF,Wiernik PH

    更新日期:1998-07-01 00:00:00

  • Proliferative response of B chronic lymphocytic leukemia lymphocytes stimulated with IL2 and soluble CD23.

    abstract::The in vitro proliferative response of purified B-chronic lymphocytic leukemia (B-CLL) lymphocytes cultured in the presence of soluble CD23 (sCD23) with or without IL2 was compared to the responses induced by phorbol 12-myristate 13-acetate (PMA), Staphylococcus aureus strain Cowan I (SAC), IL1, IL2, IL4, IL6 and the ...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199409049683

    authors: Brizard A,Morel F,Lecron JC,Dreyfus B,Brizard F,Barra A,Preud'homme JL

    更新日期:1994-07-01 00:00:00

  • Castleman's Disease and Interleukin 6.

    abstract::Castleman's disease is a rare condition characterized by benign hyperplastic lymph nodes. Based on the morphological features, it has been divided into hyaline-vascular, plasma cell and intermediate types. The latter two types are frequently associated with a wide variety of clinical pictures such as fever, anemia wit...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199009069289

    authors: Yabuhara A,Komiyama A

    更新日期:1990-01-01 00:00:00

  • Treatment of Philadelphia Chromosome Positive (Ph +) Chronic Myelogenous Leukemia in Blast Crisis and Ph + Acute Leukemia with High Dose Cytosine Arabinoside (HDARAC).

    abstract::High dose cytosine arabinoside (HDARAC) was administered to eleven patients in the blastic phase of Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML). Four patients presented in blastic phase and in seven patients blastic transformation had evolved from a previous chronic phase. All patients had...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.3109/10428199109068053

    authors: Kempin S,Arlin Z,Berman E,Gee T,Mertelsmann R,Andreeff M,Kolitz J,Jhanwar S,Myers J,Clarkson B

    更新日期:1991-01-01 00:00:00

  • Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies.

    abstract::Several surveys have defined chronic lymphocytic leukemia (CLL) patients as a high-risk patient population for developing second neoplasms. As possible mechanisms underlying the increased risk of specific second malignancies in CLL patients the immunodeficiency associated with disease is generally proposed. As far as ...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.1080/10428190400007524

    authors: Molica S

    更新日期:2005-01-01 00:00:00

  • Neutropenia and leukemia development: genetic risk factors and prognosis.

    abstract::Neutropenia is known as a clinical consequence in various genetic disorders and other neutropenia-inducing mutations (NIM) nonmalignant diseases. Leukemia development is now a major concern about the mortality of patients with congenital neutropenia. We searched the PubMed database and Google Scholar engine using Engl...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.1080/10428194.2019.1630622

    authors: Shahrabi S,Maleknia M,Tavakolifar Y,D Zayeri Z,Saki N

    更新日期:2019-12-01 00:00:00

  • Mutations within the 5' region of FAS/CD95 gene in nodal diffuse large B-cell lymphoma.

    abstract::CD95 is a cell-surface receptor that mediates apoptosis. A possible association between CD95 mutations and extranodal diffuse large B-cell lymphomas (DLBCL) has been reported. To further elucidate this question, a mutation analysis within the 5' region and exon 9 of CD95 was performed in a series of 66 DLBCL patients,...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/10428190701230858

    authors: Scholl V,Stefanoff CG,Hassan R,Spector N,Renault IZ

    更新日期:2007-05-01 00:00:00

  • Circulating clonotypic B cells in the biology of multiple myeloma: speculations on the origin of myeloma.

    abstract::The population of circulating B cells in myeloma patients includes an apparently large but variable subset with the IgH VDJ rearrangement diagnostic for the malignant clone of plasma cells in individual myeloma patients. Although the biological significance is at present unknown, it is likely that they include both ma...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.3109/10428199609054775

    authors: Pilarski LM,Masellis-Smith A,Szczepek A,Mant MJ,Belch AR

    更新日期:1996-08-01 00:00:00

  • Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib.

    abstract::Following the initial success of imatinib as frontline therapy for chronic myeloid leukemia (CML), several second-generation therapeutics have been developed with increased potency and the ability to inhibit the majority of imatinib-resistant mutations. Here, we review the current knowledge about the target specificit...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章,评审

    doi:10.1080/10428190801896103

    authors: Hantschel O,Rix U,Superti-Furga G

    更新日期:2008-04-01 00:00:00

  • Ante-mortem diagnosis of localized invasive esophageal aspergillosis in a patient with acute myeloid leukemia.

    abstract::Opportunistic infection with invasive aspergillosis (IA) is increasingly frequent in immunocompromised patients, particularly in those with hematological malignancies. In this setting, IA typically involves the lung, with extra-pulmonary involvement usually occurring in the setting of disseminated infection. We report...

    journal_title:Leukemia & lymphoma

    pub_type: 杂志文章

    doi:10.1080/10428190400025138

    authors: Chionh F,Herbert KE,Seymour JF,Prince HM,Wolf M,Zimet A,Tam C,Kennedy GA

    更新日期:2005-04-01 00:00:00