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  1. Article ; Online: ADCT-602, a Novel PBD Dimer-containing Antibody-Drug Conjugate for Treating CD22-positive Hematologic Malignancies.

    Zammarchi, Francesca / Havenith, Karin E / Sachini, Nikoleta / Janghra, Narinder / Chivers, Simon / Idusogie, Esohe / Gaudio, Eugenio / Tarantelli, Chiara / Bertelli, Francois / Santos, Kathleen / Tyrer, Peter / Corbett, Simon / Spriano, Filippo / Golino, Gaetanina / Cascione, Luciano / Bertoni, Francesco / Hartley, John A / van Berkel, Patrick H

    Molecular cancer therapeutics

    2024  Volume 23, Issue 4, Page(s) 520–531

    Abstract: Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody-drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid ... ...

    Abstract Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas have poor patient outcomes; novel therapies are needed. CD22 is an attractive target for antibody-drug conjugates (ADCs), being highly expressed in R/R B-ALL with rapid internalization kinetics. ADCT-602 is a novel CD22-targeting ADC, consisting of humanized mAb hLL2-C220, site specifically conjugated to the pyrrolobenzodiazepine dimer-based payload tesirine. In preclinical studies, ADCT-602 demonstrated potent, specific cytotoxicity in CD22-positive lymphomas and leukemias. ADCT-602 was specifically bound, internalized, and trafficked to lysosomes in CD22-positive tumor cells; after cytotoxin release, DNA interstrand crosslink formation persisted for 48 hours. In the presence of CD22-positive tumor cells, ADCT-602 caused bystander killing of CD22-negative tumor cells. A single ADCT-602 dose led to potent, dose-dependent, in vivo antitumor activity in subcutaneous and disseminated human lymphoma/leukemia models. Pharmacokinetic analyses (rat and cynomolgus monkey) showed excellent stability and tolerability of ADCT-602. Cynomolgus monkey B cells were efficiently depleted from circulation after one dose. Gene signature association analysis revealed IRAK1 as a potential marker for ADCT-602 resistance. Combining ADCT-602 + pacritinib was beneficial in ADCT-602-resistant cells. Chidamide increased CD22 expression on B-cell tumor surfaces, increasing ADCT-602 activity. These data support clinical testing of ADCT-602 in R/R B-ALL (NCT03698552) and CD22-positive hematologic cancers.
    MeSH term(s) Humans ; Rats ; Animals ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Macaca fascicularis ; Antineoplastic Agents/therapeutic use ; Lymphoma, B-Cell/drug therapy ; Hematologic Neoplasms/drug therapy ; Sialic Acid Binding Ig-like Lectin 2
    Chemical Substances Immunoconjugates ; Antineoplastic Agents ; Sialic Acid Binding Ig-like Lectin 2 ; CD22 protein, human
    Language English
    Publishing date 2024-02-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-23-0506
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: Show issues Location:
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  2. Article: A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma.

    Weiner, Amber K / Radaoui, Alexander B / Tsang, Matthew / Martinez, Daniel / Sidoli, Simone / Conkrite, Karina L / Delaidelli, Alberto / Modi, Apexa / Rokita, Jo Lynne / Patel, Khushbu / Lane, Maria V / Zhang, Bo / Zhong, Chuwei / Ennis, Brian / Miller, Daniel P / Brown, Miguel A / Rathi, Komal S / Raman, Pichai / Pogoriler, Jennifer /
    Bhatti, Tricia / Pawel, Bruce / Glisovic-Aplenc, Tina / Teicher, Beverly / Erickson, Stephen W / Earley, Eric J / Bosse, Kristopher R / Sorensen, Poul H / Krytska, Kateryna / Mosse, Yael P / Havenith, Karin E / Zammarchi, Francesca / van Berkel, Patrick H / Smith, Malcolm A / Garcia, Benjamin A / Maris, John M / Diskin, Sharon J

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor ... ...

    Abstract Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target.
    Highlights: Plasma membrane enriched proteomics defines surfaceome of neuroblastomaMulti-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancersDLK1 expression is driven by a super-enhancer
    Language English
    Publishing date 2024-01-07
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.06.570390
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Camidanlumab tesirine, an antibody-drug conjugate, in relapsed/refractory CD25-positive acute myeloid leukemia or acute lymphoblastic leukemia: A phase I study.

    Goldberg, Aaron D / Atallah, Ehab / Rizzieri, David / Walter, Roland B / Chung, Ki-Young / Spira, Alexander / Stock, Wendy / Tallman, Martin S / Cruz, Hans G / Boni, Joseph / Havenith, Karin E G / Chao, Grace / Feingold, Jay M / Wuerthner, Jens / Solh, Melhem

    Leukemia research

    2020  Volume 95, Page(s) 106385

    Abstract: There is a significant need for improved therapeutics in older patients with acute leukemia. Camidanlumab tesirine is an antibody-drug conjugate against CD25, an antigen expressed in several malignancies, including acute lymphoblastic leukemia (ALL) and ... ...

    Abstract There is a significant need for improved therapeutics in older patients with acute leukemia. Camidanlumab tesirine is an antibody-drug conjugate against CD25, an antigen expressed in several malignancies, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This open-label, dose-escalation and -expansion study (NCT02588092) assessed the safety, activity, pharmacokinetics (PK), and immunogenicity of camidanlumab tesirine in patients with relapsed/refractory ALL/AML. A total of 35 patients (34 AML and 1 ALL) were enrolled and received camidanlumab tesirine intravenously at 3-92 μg/kg once every three weeks (Q3W, n = 26) or 30 or 37.5 μg/kg every week (QW, n = 9). One dose-limiting toxicity of maculopapular rash occurred in the 30 μg/kg QW group; the maximum tolerated dose was not reached. No additional safety concerns or adverse events (AEs) of interest were identified. The most common (>10 % of patients) Grade ≥3 treatment-emergent AEs were febrile neutropenia (25.7 %), lymphopenia, neutropenia, thrombocytopenia or fatigue (all 14.3 %), pneumonia, increased gamma-glutamyltransferase, and hypophosphatemia (each 11.4 %). No signal for serious immune-related AEs such as Guillain-Barré syndrome/polyradiculopathy was observed and there was no evidence of immunogenicity. PK showed rapid clearance with apparent half-life <2 days for conjugated and total antibody, suggesting that Q3W dosing may be insufficient for therapeutic efficacy, and prompting exploration of a QW schedule. Two patients achieved complete responses with incomplete hematologic recovery; one each at 30 and 37.5 μg/kg QW. The trial was terminated during dose escalation due to programmatic reasons other than safety. Hence, recommended dose was not determined.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents, Immunological/therapeutic use ; Female ; Humans ; Immunoconjugates/therapeutic use ; Interleukin-2 Receptor alpha Subunit/antagonists & inhibitors ; Leukemia, Myeloid, Acute/drug therapy ; Male ; Maximum Tolerated Dose ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Young Adult
    Chemical Substances Antineoplastic Agents, Immunological ; IL2RA protein, human ; Immunoconjugates ; Interleukin-2 Receptor alpha Subunit
    Language English
    Publishing date 2020-06-07
    Publishing country England
    Document type Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 752396-8
    ISSN 1873-5835 ; 0145-2126
    ISSN (online) 1873-5835
    ISSN 0145-2126
    DOI 10.1016/j.leukres.2020.106385
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1321: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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