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1.
J Immunol Methods ; 512: 113406, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36526009

RESUMO

A modified biotin-drug extraction and acid dissociation (BEAD) immunogenicity assay was developed to detect anti-drug-antibodies (ADA) against the human anti-FXIIa monoclonal antibody (mAb) drug, Garadacimab (previously called CSL312). Multiple strategies were tested to optimize the signal-to-background (S/B) ratio, assay sensitivity and the drug tolerance. The modified BEAD assay was found to be highly drug tolerant (>500 µg/ml) with a sensitivity of 100 ng/ml, in line with current FDA regulatory guidelines. The assay was validated for use in a repeat-dose animal safety study and showed an acceptable intra-assay precision and robustness but a lower inter-assay precision. In-study sample analysis confirmed that the assay was fit-for-purpose (FFP) for the context-of-use (COU) in the nonclinical study and the results obtained were deemed meaningful.


Assuntos
Anticorpos Monoclonais , Biotina , Animais , Humanos , Anticorpos Monoclonais/efeitos adversos
2.
J Allergy Clin Immunol ; 149(6): 2105-2115.e10, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34968528

RESUMO

BACKGROUND: Patients with antibody deficiency suffer chronic respiratory symptoms, recurrent exacerbations, and progressive airways disease despite systemic replacement of IgG. Little is known about the respiratory tract biology of these patients. OBJECTIVE: We sought to measure immunoglobulin levels, inflammatory cytokines, and mediators of tissue damage in serum and sputum from patients with antibody deficiency and healthy controls; to analyze the respiratory microbiome in the same cohorts. METHODS: We obtained paired sputum and serum samples from 31 immunocompetent subjects and 67 antibody-deficient patients, the latter divided on computed tomography scan appearance into "abnormal airways" (bronchiectasis or airway thickening) or "normal airways." We measured inflammatory cytokines, immunoglobulin levels, neutrophil elastase, matrix-metalloproteinase-9, urea, albumin, and total protein levels using standard assays. We used V3-V4 region 16S sequencing for microbiome analysis. RESULTS: Immunodeficient patients had markedly reduced IgA in sputum but higher concentrations of IgG compared with healthy controls. Inflammatory cytokines and tissue damage markers were higher in immunodeficient patients, who also exhibited dysbiosis with overrepresentation of pathogenic taxa and significantly reduced alpha diversity compared with immunocompetent individuals. These differences were seen regardless of airway morphology. Sputum matrix-metalloproteinase-9 and elastase correlated inversely with alpha diversity in the antibody-deficient group, as did sputum IgG, which correlated positively with several inflammatory markers, even after correction for albumin levels. CONCLUSIONS: Patients with antibody deficiency, even with normal lung imaging, exhibit inflammation and dysbiosis in their airways despite higher levels of IgG compared with healthy controls.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Albuminas/análise , Biomarcadores , Citocinas , Disbiose , Humanos , Imunoglobulina G , Inflamação , Sistema Respiratório , Escarro
3.
Cancers (Basel) ; 11(7)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262047

RESUMO

About 95% of patients with Glioblastoma (GBM) show tumor relapse, leaving them with limited therapeutic options as recurrent tumors are most often resistant to the first line chemotherapy standard Temozolomide (TMZ). To identify molecular pathways involved in TMZ resistance, primary GBM Stem-like Cells (GSCs) were isolated, characterized, and selected for TMZ resistance in vitro. Subsequently, RNA sequencing analysis was performed and revealed a total of 49 differentially expressed genes (|log2-fold change| > 0.5 and adjusted p-value < 0.1) in TMZ resistant stem-like cells compared to their matched DMSO control cells. Among up-regulated genes, we identified carbonic anhydrase 2 (CA2) as a candidate gene correlated with glioma malignancy and patient survival. Notably, we describe consistent up-regulation of CA2 not only in TMZ resistant GSCs on mRNA and protein level, but also in patient-matched clinical samples of first manifest and recurrent tumors. Co-treatment with the carbonic anhydrase inhibitor Acetazolamid (ACZ) sensitized cells to TMZ induced cell death. Cumulatively, our findings illustrate the potential of CA2 as a chemosensitizing target in recurrent GBM and provide a rationale for a therapy associated inhibition of CA2 to overcome TMZ induced chemoresistance.

4.
Cell Rep ; 26(13): 3672-3683.e7, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917320

RESUMO

Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating discoidin domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents.


Assuntos
Proteínas 14-3-3/metabolismo , Proteína Beclina-1/metabolismo , Neoplasias Encefálicas/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Glioblastoma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Autofagia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Linhagem Celular , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Masculino , Camundongos , Camundongos Nus , Prognóstico , Tolerância a Radiação , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
5.
J Neuropathol Exp Neurol ; 76(10): 838-847, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922853

RESUMO

Glioblastoma (GBM) is the most common malignant primary brain tumor. It still carries a grim prognosis and new therapies are needed. This review summarizes the current status of mechanistic insights into the function of extracellular regulated kinase (ERK) and its potential as a therapeutic target for patients with GBM. Currently, some promising ERK inhibitors are in clinical trials in tumor entities other than GBM. Here, we provide a comprehensive overview on the functions of ERK1/2 in GBM and a rationale for treatment of GBM with ERK inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Inibidores Enzimáticos/uso terapêutico , Glioblastoma/terapia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Humanos
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