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  • 1
    Online Resource
    Online Resource
    AMG 595, an Anti-EGFRvIII Antibody–Drug Conjugate, Induces Potent Antitumor Activity against EGFRvIII-Expressing Glioblastoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 7 ( 2015-07-01), p. 1614-1624
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 7 ( 2015-07-01), p. 1614-1624
    Abstract: Epidermal growth factor receptor variant III (EGFRvIII) is a cancer-specific deletion mutant observed in approximately 25% to 50% of glioblastoma multiforme (GBM) patients. An antibody drug conjugate, AMG 595, composed of the maytansinoid DM1 attached to a highly selective anti-EGFRvIII antibody via a noncleavable linker, was developed to treat EGFRvIII-positive GBM patients. AMG 595 binds to the cell surface and internalizes into the endo-lysosomal pathway of EGFRvIII-expressing cells. Incubation of AMG 595 with U251 cells expressing EGFRvIII led to potent growth inhibition. AMG 595 treatment induced significant tumor mitotic arrest, as measured by phospho-histone H3, in GBM subcutaneous xenografts expressing EGFRvIII. A single intravenous injection of AMG 595 at 17 mg/kg (250 μg DM1/kg) generated complete tumor regression in the U251vIII subcutaneous xenograft model. AMG 595 mediated tumor regression in the D317 subcutaneous xenograft model that endogenously expresses EGFRvIII. Finally, AMG 595 treatment inhibited the growth of D317 xenografts orthotopically implanted into the brain as determined by magnetic resonance imaging. These results demonstrate that AMG 595 is a promising candidate to evaluate in EGFRvIII-expressing GBM patients. Mol Cancer Ther; 14(7); 1614–24. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-14-1078
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
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  • 2
    Online Resource
    Online Resource
    Mo2012 Augmentation of Colonic Inflammation by TL1A is Most Severe in the Presence of a Genetic Susceptibility and Bacterial Trigger
    Elsevier BV ; 2012
    In:  Gastroenterology Vol. 142, No. 5 ( 2012-05), p. S-720-
    Details
    In: Gastroenterology, Elsevier BV, Vol. 142, No. 5 ( 2012-05), p. S-720-
    Type of Medium: Online Resource
    ISSN: 0016-5085
    URL: Article
    DOI: 10.1016/S0016-5085(12)62792-9
    RVK:
    XA 44500
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
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  • 3
    Online Resource
    Online Resource
    SGN-B6A: A New Vedotin Antibody-Drug Conjugate Directed to Integrin Beta-6 for Multiple Carcinoma Indications
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics ( 2023-08-25)
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), ( 2023-08-25)
    Abstract: Integrin beta-6, a component of the heterodimeric adhesion receptor alpha-v/beta-6, is overexpressed in numerous solid tumors. Its expression has been shown by multiple investigators to be a negative prognostic indicator in diverse cancers including colorectal, non-small cell lung, gastric, and cervical. We developed SGN-B6A as an antibody-drug conjugate (ADC) directed to integrin beta-6 to deliver the clinically validated payload monomethyl auristatin E (MMAE) to cancer cells. The antibody component of SGN-B6A is specific for integrin beta-6 and does not bind other alpha-v family members. In preclinical studies, this ADC has demonstrated activity in vivo in models derived from non-small cell lung, pancreatic, pharyngeal, and bladder carcinomas spanning a range of antigen expression levels. In nonclinical toxicology studies in cynomolgus monkeys, doses of up to 5 mg/kg weekly for four doses or 6 mg/kg every 3 weeks for two doses were tolerated. Hematologic toxicities typical of MMAE ADCs were dose limiting, and no significant target-mediated toxicity was observed. A phase 1 first-in-human study is in progress to evaluate the safety and antitumor activity of SGN-B6A in a variety of solid tumors known to express integrin beta-6 (NCT04389632).
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-22-0817
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2062135-8
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  • 4
    Online Resource
    Online Resource
    Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics ( 2023-09-30)
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), ( 2023-09-30)
    Abstract: Brentuximab vedotin, a CD30-directed antibody–drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the “gold standard” test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous EBV-reactive CD8+ T cells potentiating the activity of anti–PD-1 therapy. Together these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-23-0118
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2062135-8
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  • 5
    Online Resource
    Online Resource
    Expression of Trop2 Cell Surface Glycoprotein in Normal and Tumor Tissues : Potential Implications as a Cancer Therapeutic Target
    SAGE Publications ; 2011
    In:  Journal of Histochemistry & Cytochemistry Vol. 59, No. 7 ( 2011-07), p. 701-710
    Details
    In: Journal of Histochemistry & Cytochemistry, SAGE Publications, Vol. 59, No. 7 ( 2011-07), p. 701-710
    Abstract: Trop2 is a cell-surface glycoprotein reported to be overexpressed in various types of adenocarcinomas with minimal expression in normal tissues. Recent findings that Trop2 expression correlates with tumor aggressiveness have increased interest in Trop2 as a potential target for cancer immunotherapy. The goal of this study was to extensively evaluate Trop2 expression at the transcript and protein levels in normal and tumor tissues. It was determined that Trop2 is overexpressed on some carcinomas relative to the corresponding normal tissue. However, in human and mouse, Trop2 is highly expressed at both the transcript and protein levels on several essential normal tissues. The findings suggest that the development of therapeutic agents to target Trop2 may require strategies that target Trop2 on malignant tissues in order to minimize potential toxicities to essential normal tissues that also express high levels of Trop2.
    Type of Medium: Online Resource
    ISSN: 0022-1554 , 1551-5044
    URL: Article
    DOI: 10.1369/0022155411410430
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2011
    detail.hit.zdb_id: 1421306-0
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  • 6
    Online Resource
    Online Resource
    Fibrotic footprint of Oncostatin M-induced pulmonary disease (97.10)
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 1_Supplement ( 2009-04-01), p. 97.10-97.10
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 1_Supplement ( 2009-04-01), p. 97.10-97.10
    Abstract: Oncostatin M (OSM), an IL-6 family cytokine, has been implicated in a number of biological processes including the induction of inflammation and modulation of extracellular matrix (ECM). Recently, we observed that OSM is elevated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis as well as scleroderma. In mice, delivery of OSM to the lungs results in recruitment of inflammatory cells and an increase in collagen deposition in the lungs, with pathological correlates to characteristic human interstitial lung disease. We used genetically modified mice to show that the fibrotic response is largely independent of B and T lymphocytes, eosinophils and mast cells. To investigate the relationship between OSM-induced inflammation and OSM-induced fibrosis, we used both protein and genomic array approaches to generate a "fibrotic footprint" for OSM. While the IL-4/IL-13 and TGF-β pathways are generally intertwined in fibrosis, we show that OSM is capable of driving lung fibrosis independent of these pathways. For comparison, we show the expression patterns of OSM versus bleomycin-induced lung fibrosis to highlight the unique mechanisms underlying disease pathogenesis. The demonstration that OSM is a potent mediator of lung inflammation and ECM accumulation, and upregulated in patients, provides a rationale for targeting OSM in human disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.Supp.97.10
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    B-Lymphocyte Proliferation during Bovine Leukemia VirusInduced Persistent Lymphocytosis Is Enhanced by T-Lymphocyte-Derived Interleukin-2
    American Society for Microbiology ; 1998
    In:  Journal of Virology Vol. 72, No. 4 ( 1998-04), p. 3169-3177
    Details
    In: Journal of Virology, American Society for Microbiology, Vol. 72, No. 4 ( 1998-04), p. 3169-3177
    Abstract: Bovine leukemia virus (BLV)-induced persistent lymphocytosis is characterized by a polyclonal expansion of CD5 + B lymphocytes. To examine the role of the cytokine microenvironment in this virus-induced B-lymphocyte expansion, the expression of interleukin-2 (IL-2), IL-4, IL-10, and gamma interferon (IFN-γ) mRNA, was measured in stimulated peripheral blood mononuclear cells from persistently lymphocytotic BLV-infected cows, nonlymphocytotic BLV-infected cows, and uninfected cows. IL-2 and IL-10 mRNA expression and IL-2 functional activity were significantly increased when peripheral blood mononuclear cells from persistently lymphocytotic cows were stimulated with concanavalin A (ConA). Additionally, during persistent lymphocytosis, peak IL-2 and IL-10 mRNA expression was delayed, and elevated expression was prolonged. To determine the potential biologic importance of increased IL-2 and IL-10 expression, the response of isolated B lymphocytes from persistently lymphocytotic cows to human recombinant cytokines and to cytokine-containing supernatants from isolated T lymphocytes was examined. While recombinant human IL-10 (rhIL-10) did not consistently induce detectable changes, rhIL-2 increased viral protein (p24) and IL-2 receptor expression in isolated B lymphocytes from persistently lymphocytotic cows. Additionally, rhIL-2 and supernatant from ConA-stimulated T lymphocytes enhanced B-lymphocyte proliferation. The stimulatory activity of the T-lymphocyte supernatant could be completely inhibited with a polyclonal anti-rhIL-2 antibody. Finally, polyclonal anti-rhIL-2 antibody, as well as anti-BLV antibody, inhibited spontaneous proliferation of peripheral blood mononuclear cells from persistently lymphocytotic cows, demonstrating that the spontaneous lymphoproliferation characteristic of BLV-induced persistent lymphocytosis is IL-2 dependent and antigen dependent. Collectively, these findings strongly suggest that increased T-lymphocyte expression of IL-2 in BLV-infected cows contributes to development and/or maintenance of persistent B lymphocytosis.
    Type of Medium: Online Resource
    ISSN: 0022-538X , 1098-5514
    URL: Article
    DOI: 10.1128/JVI.72.4.3169-3177.1998
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1998
    detail.hit.zdb_id: 1495529-5
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  • 8
    Online Resource
    Online Resource
    253
    Elsevier BV ; 2013
    In:  Cytokine Vol. 63, No. 3 ( 2013-09), p. 303-
    Details
    In: Cytokine, Elsevier BV, Vol. 63, No. 3 ( 2013-09), p. 303-
    Type of Medium: Online Resource
    ISSN: 1043-4666
    URL: Article
    DOI: 10.1016/j.cyto.2013.06.256
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 1463198-2
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Mechanisms of Oncostatin M-Induced Pulmonary Inflammation and Fibrosis
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 181, No. 10 ( 2008-11-15), p. 7243-7253
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 181, No. 10 ( 2008-11-15), p. 7243-7253
    Abstract: Oncostatin M (OSM), an IL-6 family cytokine, has been implicated in a number of biological processes including the induction of inflammation and the modulation of extracellular matrix. In this study, we demonstrate that OSM is up-regulated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and scleroderma, and investigate the pathological consequences of excess OSM in the lungs. Delivery of OSM to the lungs of mice results in a significant recruitment of inflammatory cells, as well as a dose-dependent increase in collagen deposition in the lungs, with pathological correlates to characteristic human interstitial lung disease. To better understand the relationship between OSM-induced inflammation and OSM-induced fibrosis, we used genetically modified mice and show that the fibrotic response is largely independent of B and T lymphocytes, eosinophils, and mast cells. We further explored the mechanisms of OSM-induced inflammation and fibrosis using both protein and genomic array approaches, generating a “fibrotic footprint” for OSM that shows modulation of various matrix metalloproteinases, extracellular matrix components, and cytokines previously implicated in fibrosis. In particular, although the IL-4/IL-13 and TGF-β pathways have been shown to be important and intertwined of fibrosis, we show that OSM is capable of inducing lung fibrosis independently of these pathways. The demonstration that OSM is a potent mediator of lung inflammation and extracellular matrix accumulation, combined with the up-regulation observed in patients with pulmonary fibrosis, may provide a rationale for therapeutically targeting OSM in human disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.181.10.7243
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 10
    Online Resource
    Online Resource
    Development of Novel Antibody–Camptothecin Conjugates
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Therapeutics Vol. 20, No. 2 ( 2021-02-01), p. 329-339
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 2 ( 2021-02-01), p. 329-339
    Abstract: We have developed a highly active and well-tolerated camptothecin (CPT) drug-linker designed for antibody-mediated drug delivery in which the lead molecule consists of a 7-aminomethyl-10,11-methylenedioxy CPT (CPT1) derivative payload attached to a novel hydrophilic protease-cleavable valine–lysine–glycine tripeptide linker. A defined polyethylene glycol stretcher was included to improve the properties of the drug-linker, facilitating high antibody–drug conjugate (ADC) drug loading, while reducing the propensity for aggregation. A CPT1 ADC with 8 drug-linkers/mAb displayed a pharmacokinetic profile coincident with parental unconjugated antibody and had high serum stability. The ADCs were broadly active against cancer cells in vitro and in mouse xenograft models, giving tumor regressions and complete responses at low (≤3 mg/kg, single administration) doses. Pronounced activities were obtained in both solid and hematologic tumor models and in models of bystander killing activity and multidrug resistance. Payload release studies demonstrated that two CPTs, CPT1 and the corresponding glycine analog (CPT2), were released from a cAC10 ADC by tumor cells. An ADC containing this drug-linker was well tolerated in rats at 60 mg/kg, given weekly four times. Thus, ADCs comprised of this valine–lysine–glycine linker with CPT drug payloads have promise in targeted drug delivery.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-20-0526
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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