A5038935034- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Immune cells in cancer
- Cancer, Stress, Anesthesia, and Immune Response
- Immune Response and Inflammation
- T-cell and B-cell Immunology
- Cytokine Signaling Pathways and Interactions
- Immunotherapy and Immune Responses
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Complement system in diseases
- TGF-β signaling in diseases
- PI3K/AKT/mTOR signaling in cancer
- Systemic Lupus Erythematosus Research
- CAR-T cell therapy research
- Cancer Mechanisms and Therapy
- NF-κB Signaling Pathways
- Chronic Myeloid Leukemia Treatments
- Kruppel-like factors research
- Cancer-related Molecular Pathways
- Wnt/β-catenin signaling in development and cancer
- Galectins and Cancer Biology
- Renal cell carcinoma treatment
- PARP inhibition in cancer therapy
- Cancer-related gene regulation
- Immunotoxicology and immune responses
Ono Pharmaceutical (United States)
2019-2023
Research & Development Institute
2021
AstraZeneca (United States)
2008-2018
Acceleron Pharma (United States)
2013-2016
AstraZeneca (United Kingdom)
2013
Boston Children's Hospital
2013
Harvard University
2004-2012
Boston University
2008
Boston Biomedical Research Institute
2008
University of Cologne
1999-2006
Programmed cell-death 1 ligand (PD-L1) is a member of the B7/CD28 family proteins that control T-cell activation. Many tumors can upregulate expression PD-L1, inhibiting antitumor responses and avoiding immune surveillance elimination. We have identified characterized MEDI4736, human IgG1 monoclonal antibody binds with high affinity specificity to PD-L1 uniquely engineered prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate MEDI4736 potent antagonist function,...
The tumor necrosis factor (TNF) family cytokines lymphotoxin (LT) α and LTβ form heterotrimers that are expressed on the surface of activated lymphocytes natural killer cells; LTα homotrimers can be secreted as well. Mice with a disrupted gene lack lymph nodes (LN), Peyer’s patches (PP), follicular dendritic cell (FDC) networks reveal profound defects splenic architecture. However, it is unclear which these abnormalities result absence in or LTαβ heterotrimers. To distinguish between two...
The formation of germinal centers (GCs) represents a crucial step in the humoral immune response. Recent studies using gene-targeted mice have revealed that cytokines tumor necrosis factor (TNF), lymphotoxin (LT) alpha, and LTbeta, as well their receptors TNF receptor p55 (TNFRp55) LTbetaR play essential roles development GCs. To establish which cell types expression LTbetaR, is required for GC formation, LTbetaR-/-, LTbeta-/-, TNF-/-, B cell-deficient (BCR-/-), wild-type were used to...
The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion one or more myeloid lineages. discovery the Jak2 V617F gain function mutation highlighted as potential therapeutic target in MPNs. Herein, we disclose series pyrazol-3-yl pyrimidin-4-amines identification 9e (AZD1480) potent inhibitor. inhibits signaling proliferation cell lines...
Nonhomologous end-joining (NHEJ) repairs DNA double-strand breaks (DSBs) during V(D)J recombination in developing lymphocytes and immunoglobulin (Ig) heavy chain (IgH) class switch (CSR) peripheral B lymphocytes. We now show that CD21-cre–mediated deletion of the Xrcc4 NHEJ gene p53-deficient cells leads to recurrent surface Ig-negative lymphomas (“CXP lymphomas”). Remarkably, CXP arise from had attempted both receptor editing (secondary V[D]J Igκ Igλ light genes) IgH CSR subsequent...
The Wnt pathway is an evolutionarily conserved and tightly regulated signaling network with important roles in embryonic development adult tissue regeneration. Impaired regulation, arising from mutations components, such as Axin, APC, β-catenin, results uncontrolled cell growth triggers oncogenesis. To explore the reported link between CK2 kinase activity signaling, we sought to identify a potent, selective inhibitor of suitable for proof concept studies vivo. Starting...
Structure based design, synthesis, and biological evaluation of a novel series 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using C-ring fragment from our first clinical candidate AZD1480 (24), optimization led discovery compound 19a, potent, orally bioavailable inhibitor. Compound 19a displayed high level cellular activity in hematopoietic cell lines harboring V617F mutation murine BaF3 TEL-Jak2 cells. demonstrated significant tumor...
In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors CK2 kinase. Property-based optimization early leads using 7-oxetan-3-yl amino group led to a series matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, reduced binding hERG ion channel. Agents in study were shown modulate pAKT(S129), direct substrate CK2, vitro vivo, exhibited tumor growth inhibition when...
The factors that allow self‐reactive B cells to escape negative selection and become activated remain poorly defined. Using a BCR knock‐in mouse strain, we identify pathway by which ‐cell nucleolar self‐antigens is complement dependent. Deficiency in component C 4 led breakdown the elimination of autoreactive clones at transitional stage, characterized relative increase their response range stimuli, entrance into follicles, greater propensity form GC s. mixed BM chimeras, found myeloid...
Abstract Inactivation of genes encoding members TNF and receptor families reveal their divergent roles in the formation function secondary lymphoid organs. Most lymphotoxin α (ltα)- all β (ltβr)-deficient mice are completely devoid lymph nodes (LNs); however, most (ltβ)-deficient develop mesenteric LNs. Tnf- tnfrp55-deficient a complete set LNs, while ltβ/tnfrp55 double-deficient lack demonstrating cooperation between LTβ TNFRp55 LN development. Now we report that ltβ/tnf same mucosal LNs as...
Homologous genes and gene products often have redundant physiological functions. Members of the tumor necrosis factor (TNF) family cytokines can signal activation, proliferation, differentiation, costimulation, inhibition, or cell death, depending on type status target cell. TNF, lymphotoxin alpha (LTalpha), LTbeta form a subfamily larger TNF-related ligands with their being linked within compact 12-kb cluster inside major histocompatibility complex locus. Singly TNF-, LTalpha-,...
Treatment of metastatic renal cell carcinoma (mRCC) with agents that block signaling through vascular endothelial growth factor receptor 2 (VEGFR2) induces disease regression or stabilization in some patients; however, these responses tend to be short-lived. Therefore, development combination therapies can extend the efficacy VEGFR antagonists mRCC remains a priority.We studied murine xenograft models RCC become refractory treatment tyrosine kinase inhibitor (TKI) sunitinib. Dalantercept is...
Tumor necrosis factor alpha (TNF-alpha) and soluble lymphotoxin (LT) (also called LT-alpha or TNF-beta) are cytokines with similar biological activities that encoded by related closely linked genes. TNF-alpha, a mediator of the inflammatory response, exists in transmembrane forms. can be secreted retained at cell surface binding to 33-kDa subunit, LT-beta. The recently cloned human LT-beta gene encodes another TNF family member is TNF/LT locus within major histocompatibility complex locus....
Janus kinases (JAKs) have been demonstrated to be critical in cytokine signaling and thus implicated both cancer inflammatory diseases. The JAK family consists of four highly homologous members: JAK1–3 TYK2. development small-molecule inhibitors that are selective for a specific member would represent desirable tools deconvoluting the intricacies biology. Herein, we report discovery potent JAK1 inhibitor, 24, which displays ∼1000-fold selectivity over other members (determined by biochemical...
Membrane lymphotoxin (LT) complex is a trimer composed of two subunits , LT-alpha and LT-beta which the latter 33-kDa transmembrane protein. The gene expressed in lymphoid cells organs, but little known about its inducible regulation. Previously, surface expression Jurkat has been shown to increase response PMA. In this report, we used model study transcriptional control human murine genes. PMA strongly induced mRNA, level induction was not changed markedly by cycloheximide (CHX) treatment....