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#28972490   2017/10/03 Save this To Up

PHAGOCYTOSIS AND EXPRESSION OF FCg-RECEPTORS AND CD180 ON MONOCYTES IN CHRONIC LYMPHOCYTIC LEUKEMIA.

Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disease characterised by accumulation of monoclonal CD19+CD5+CD23+ lymphocytes in the peripheral blood and bone marrow. CLL is the most common type of the adult leukemia in the Western world. The disease is incurable, albeit there are new molecular and immunotherapy methods currently available in conjunction with chemotherapy, leading to the "precision therapy". The majority of immunotherapeutic approaches are based on the ability of therapeutic antibodies (Rituximab, Alemtuzumab) to mobilize anti-tumour potential of the Natural Killer cells and macrophages/monocytes through their Fcg-receptors (FcγR). Therefore functional status of monocytes in CLL is an important contributor to the efficacy of this treatment. In addition, CLL patients are characterized by a profound immunodeficiency, and how this affects monocytes, has not been established. Here we study ex vivo phagocytic function and the expression of Fcg receptors and CD180 toll-like receptor (TLR) by monocytes of 14 untreated and 8 treated with Cyclophosmamide, Adriamycin, Prednisolone (COP) CLL patients, and 12 age-matched control volunteers. Phagocytic function was assessed through the ability of freshly isolated monocytes to attach and to engulf intact or opsonized Staphylococcus aureus particles in vitro with or without Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) and Interferon g (IFNg). Simultaneously, immunophenotyping for FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16) and CD180 has been carried out. The results were assessed by Flow Cytometry. Our results demonstrated that phagocytosis of the intact and opsonised or intact S. aureus by monocytes of CLL patients was significantly decreased in comparison with normal controls, with no recovery upon the treatment with GM-CSF and IFNg. A significant decrease in the expression of CD64 and CD180 has been detected on monocytes of CLL patients, with the drop in CD64 expression correlating with the disease progression and advanced Rai stages. In addition, the treatment with COP led to a more profound decrease in the expression of CD64. No appreciable changes were detected in the expression of CD32 and CD16 throughout the experiments. The diminished expression of CD64 and CD180 provides possible explanation for the impaired phagocytic function of monocytes in CLL, as FcγRI receptor interaction with opsonising IgG1, and CD180 with the ligands on S. aureus might affect the ability of monocytes to attach and to engulf S. aureus particles and effectively eliminate the pathogen. Our data indicates that the decreased functional status of monocytes in CLL might contribute to the diminished efficacy of therapeutic antibodies as well as to the immunodeficiency, characteristic for these patients.

1340 related Products with: PHAGOCYTOSIS AND EXPRESSION OF FCg-RECEPTORS AND CD180 ON MONOCYTES IN CHRONIC LYMPHOCYTIC LEUKEMIA.

DNA (cytosine 5) methyltr Androgen Receptor (Phosph Androgen Receptor (Phosph Rabbit Anti-Human Androge Rabbit Anti-Human Androge Androgen Receptor (Ab 650 Anti 3 DG imidazolone Mon AZD-3514 Mechanisms: Andr 17β-Acetoxy-2α-bromo-5 (5α,16β)-N-Acetyl-16-[2 (5α,16β)-N-Acetyl-16-ac 5α-N-Acetyl-2'H-androst-

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#28847264   2017/08/29 Save this To Up

Pre- and Posttransplant Refractory Idiopathic Membranous Glomerulonephritis: The Forgotten Potential Culprit.

Idiopathic membranous nephropathy has been recently recognized as an autoimmune disease that may recur or develop de novo posttransplant, whereby specific auto- or alloantibodies are directed against recently recognized podocyte structures such as the phospholipase receptor PLAR2 and the thrombospondin receptor THSD7A. The observed inconsistencies in therapeutic responses with all presently recognized therapies irrespective of immunosuppressive regimen used and the superiority of complete and sustained remission rates in recurrent disease after kidney transplant compared with native disease imply the existence of different immunopathogenic signatures that may be operational, either isolated or combined, in the pathogenesis of membranous nephropathy. These pathogenic mechanisms involve primarily B-cell-mediated pathways with a T-cell help component and distinct auto- and alloantibody-secreting mechanisms involving different B cells. These pathways are present in separate compartments such as in CD20+-activated B cells found in spleen and lymph nodes, CD19+/CD20- plasmablasts and short-lived plasma cells in the blood, and CD19-/CD20-/CD38+/CD138+ long-lived memory plasma cells niched naturally in the bone marrow and ectopically in the native or grafted inflamed kidney. These latter nonproliferating plasma cells lacking CD19 and CD20 markers would be resistant to in vivo B-cell depletion by anti-CD20 monoclonal therapies. They produce considerable amounts of immunoglobulin G (IgG) autoantibodies and alloantibodies and provide the basis for humoral memory and refractory autoimmune diseases. This may explain the limited rate of sustained complete remission, which, as observed in most studies, does not exceed a rate of 20% in all rituximab-treated patients despite total B-cell eradication. There is an important need for the development of new biomarkers to help identify and predict therapeutic responses. Potential new therapeutic targets against plasma cells such as proteasome inhibitors, anti-CD38 monoclonal antibodies, and autoreactive pathogenic B-cell-specific depleting regimens, as well as new anti-CD20 monoclonal antibodies, may help tailor therapy to the individual need for optimal outcome.

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BACTERIOLOGY BACTEROIDES Androgen Receptor (Phosph Androgen Receptor (Phosph Rabbit Anti-Human Androge Rabbit Anti-Human Androge Androgen Receptor (Ab 650 TCP-1 theta antibody Sour Recombinant Thermostable Recombinant Thermostable Recombinant Thermostable Recombinant Human PKC the Recombinant Human PKC the

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#28506291   2017/05/16 Save this To Up

Targeting CD22 with the monoclonal antibody epratuzumab modulates human B-cell maturation and cytokine production in response to Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) signaling.

Abnormal B-cell activation is implicated in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). The B-cell surface molecule CD22, which regulates activation through the B-cell receptor (BCR), is a potential target for inhibiting pathogenic B cells; however, the regulatory functions of CD22 remain poorly understood. In this study, we determined how targeting of CD22 with epratuzumab (Emab), a humanized anti-CD22 IgG1 monoclonal antibody, affects the activation of human B-cell subsets in response to Toll-like receptor 7 (TLR7) and BCR engagement.

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#27424629   2016/07/18 Save this To Up

Pharmacokinetics, Pharmacodynamics and Preliminary Observations for Clinical Activity and Safety of Multiple Doses of Human Mouse Chimeric Anti-CD22 Monoclonal Antibody (SM03) in Chinese Patients with Systemic Lupus Erythematosus.

SM03 is a novel recombinant, human/mouse chimeric immunoglobulin G1 monoclonal antibody directed against the CD22 antigen on human B lymphocytes. This was the first study to investigate the pharmacokinetics, pharmacodynamics, immunogenicity, safety and clinical activity of SM03 in patients with systemic lupus erythematosus (SLE).

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MOUSE ANTI HUMAN CD15, Pr MOUSE ANTI HUMAN CD19 RPE MOUSE ANTI HUMAN CD15, Pr MOUSE ANTI BOVINE ROTAVIR Anti AGO2 Human, Monoclon Anti AGO2 Mouse, Monoclon Anti AGO2 Human, Monoclon Anti AGO2 Mouse, Monoclon anti CD16 monoclonal anti anti CD20 monoclonal anti MOUSE ANTI BORRELIA BURGD Rabbit Anti-intestinal FA

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#27431746   2016/09/07 Save this To Up

Treatment of IgG4-related disease : Current and future approaches.

IgG4-related disease (IgG4-RD) is capable of causing great morbidity and even mortality if the condition remains undiagnosed or poorly treated, yet is typically a treatment-responsive disorder. Glucocorticoids have not been studied rigorously and practices with regard to dosing and duration of treatment remain largely empiric. In addition, IgG4-RD patients are often particularly susceptible to and intolerant of the deleterious effects of glucocorticoid therapy. B cell depletion with anti-CD20 monoclonal antibodies appears to be a rapid, effective means of obtaining disease control and limiting patients' glucocorticoid exposure, but this option is frequently not available. Other therapies targeting the B cell lineage may also be efficacious, and one is under study. The means by which depletion or inhibition of B cells and their progeny ameliorate IgG4-RD is coming into focus now through careful mechanistic studies of samples from treated patients. The mechanistic understanding of IgG4-RD will bring an array of specific targets for therapeutic intervention. Plasmablast-directed therapy with a CD19 monoclonal antibody is currently in clinical trials. CD4 + cytotoxic T lymphocytes and fibrosis, both observed nearly universally in the tissue of IgG4-RD patients, present two unexploited vulnerabilities in controlling and even reversing the effects of the disease. Further development of such therapies is a major goal of the next few years.

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#27163209   2016/06/06 Save this To Up

Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice.

B cell depletion therapy is beneficial for patients with B cell malignancies and autoimmune diseases. CD19, a transmembrane protein, is expressed on a vast majority of normal and neoplastic B cells, making it a suitable target for monoclonal antibody (MAb) mediated immunotherapy. We have developed MEDI-551, an affinity optimized and afucosylated IgG1 MAb targeting human CD19 for B cell depletion. MEDI-551 is currently under investigation in multiple clinical trials. Because MEDI-551 does not cross react with rodent and non-human primate CD19, the pharmacological characteristics of the MAb were evaluated in human CD19 transgenic mice (hCD19 Tg). Here we show that MEDI-551 potently depletes tissue and circulating B cells in hCD19 Tg mice and is more efficacious than the anti-CD19 MAb with intact fucose. The length of B cell depletion depends on MEDI-551 dose; and, B cell recovery in the circulation follows stepwise phenotypic maturation. Furthermore, intravenous (IV) and subcutaneous (SC) administration of MEDI-551 results in comparable efficacy. Lastly, the combination of MEDI-551 with the anti-CD20 MAb, rituximab, further prolongs the duration of B cell depletion. In summary, the pharmacological profile of MEDI-551 presented in hCD19 Tg mice supports further testing of MEDI-551 in clinical trials involving B cell malignancies and autoimmune diseases.

1767 related Products with: Pharmacological profile of MEDI-551, a novel anti-CD19 antibody, in human CD19 transgenic mice.

MOUSE ANTI HUMAN CD19 RPE Anti C Reactive Protein A Anti AGO2 Human, Monoclon Anti AGO2 Human, Monoclon anti CD19 IgG1 monoclonal Goat Anti-Human CD192, N- Goat Anti-Human CD194 Goat Anti-Human CD195, N- Mouse Anti-Human CD196 Goat Anti-Human CD196 CCR7(CD197) Antibody Sour CCR5(CD195) Antibody Sour

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#27040766   2016/05/02 Save this To Up

Tetravalent anti-CD20/CD3 bispecific antibody for the treatment of B cell lymphoma.

Bispecific antibodies (bsAbs) are second generation antibodies for therapeutic application in immunotherapy. One of the major strategies of the bsAb platform is the recruitment of immune effector T cells by incorporating an anti-CD3 domain. A bispecific T-cell engager (BiTE), with one end having an affinity for CD3 and the other end with affinity for CD19, has been approved in the US and Europe for the treatment of acute lymphoblastic leukemia. However, due to their small size and lack of Fc region, these single-chain variable fragment (scFv) bsAbs have short half-lives in vivo. Additionally, poor solubility, structural instability, and low production yields have also become major challenges in the bulk production process. To overcome these challenges, we have engineered a tetravalent bsAb with bivalent binding specificity for the CD20 and CD3 antigen in an immunoglobulin G (IgG) format. The fusion of the anti-CD3 scFvs to the CD20 antibody via a linker-hinge domain (LHD) results in improved antibody stabilization and properties. Here we demonstrate this antibody's highly efficient cancer cell elimination in a dose-dependent manner in a CD20-expressing B lymphoblastoid cell line in vitro. Our data suggest the potential clinical application of this bsAb for the treatment of CD20-expressing B cell malignancies.

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CRC3 CD3 (bispecific) Cl Anti C Reactive Protein A MOUSE ANTI BOVINE ROTAVIR anti CD20 monoclonal anti Signal Transduction Anti MOUSE ANTI BORRELIA BURGD RABBIT ANTI GSK3 BETA (pS Rabbit Anti-CD20 Polyclon Rabbit Anti-CD31 PECAM-1 Rabbit Anti-CD31 PECAM-1 Rabbit Anti-EpCAM CD326 P Rabbit Anti-EpCAM CD326 P

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#26671084   2015/12/16 Save this To Up

The effect of B-cell depletion in the Theiler's model of multiple sclerosis.

B cell depletion (BCD) is being considered as a treatment for multiple sclerosis (MS), but there are many uncertainties surrounding the use of this therapy, such as its potential effect in individuals with concurrent viral infections. We sought to discover what effect BCD, induced by an anti-CD20 monoclonal antibody, would have on Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Mice were injected with the anti-CD20 monoclonal antibody 5D2, 14 days before or 14 days after infection with TMEV. Efficacy of depletion of B cells was assessed by flow cytometry of CD19(+) cells. Mouse disability was measured by Rotarod, viral load was measured by real time PCR for TMEV RNA. Binding and neutralizing antibody levels were determined in sera and CSF by ELISA, and in CNS by real time PCR for IgG RNA. Inflammation, microglial activation, axonal damage and demyelination were assessed using immunohistochemistry. 5D2-induced BCD was confirmed by demonstration of nearly absent CD19(+) cells in the blood and lymphoid tissue. Systemic and CNS antibody responses were suppressed during 5D2 treatment. Higher viral loads were detected in 5D2-treated mice than in controls, and the viral levels correlated negatively with IgG production in the brain. Overall, 5D2 caused worsening of the early encephalitis and faster progression of disability, as well as exacerbation of the pathology of TMEV-IDD at the end stage of the disease. These data indicate that BCD in humans might worsen CNS viral infections and might not improve disability accrual in MS.

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#26606525   2016/03/30 Save this To Up

MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19.

To evaluate treatment with MEDI-551, a humanized anti-human CD19 monoclonal antibody, in a model of autoimmunity involving mice transgenic (Tg) for Sle1 and human CD19 (hCD19).

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Anti C Reactive Protein A Bovine Androstenedione,AS Bone Morphogenetic Protei Growth Differentiation Fa CELLKINES Natural Human I Human Macrophage Inflamma Human Macrophage Inflamma Human Epstein-Barr Virus Human Interleukin-1-beta Human Gro g Macrophage In Goat Anti-Human BMAL1 ARN Goat Anti-Human Bin3, (in

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#25856201   2015/06/01 Save this To Up

Design of Coltuximab Ravtansine, a CD19-Targeting Antibody-Drug Conjugate (ADC) for the Treatment of B-Cell Malignancies: Structure-Activity Relationships and Preclinical Evaluation.

Coltuximab ravtansine (SAR3419) is an antibody-drug conjugate (ADC) targeting CD19 created by conjugating a derivative of the potent microtubule-acting cytotoxic agent, maytansine, to a version of the anti-CD19 antibody, anti-B4, that was humanized as an IgG1 by variable domain resurfacing. Four different linker-maytansinoid constructs were synthesized (average ∼3.5 maytansinoids/antibody for each) to evaluate the impact of linker-payload design on the activity of the maytansinoid-ADCs targeting CD19. The ADC composed of DM4 (N(2')-deacetyl-N(2')-[4-mercapto-4-methyl-1-oxopentyl]maytansine) conjugated to antibody via the N-succinimidyl-4-(2-pyridyldithio)butyrate (SPDB) linker was selected for development as SAR3419. A molar ratio for DM4/antibody of between 3 and 5 was selected for the final design of SAR3419. Evaluation of SAR3419 in Ramos tumor xenograft models showed that the minimal effective single dose was about 50 μg/kg conjugated DM4 (∼2.5 mg/kg conjugated antibody), while twice this dose gave complete regressions in 100% of the mice. SAR3419 arrests cells in the G2/M phase of the cell cycle, ultimately leading to apoptosis after about 24 h. The results of in vitro and in vivo studies with SAR3419 made with DM4 that was [(3)H]-labeled at the C20 methoxy group of the maytansinoid suggest a mechanism of internalization and intracellular trafficking of SAR3419, ultimately to lysosomes, in which the antibody is fully degraded, releasing lysine-N(ε)-SPDB-DM4 as the initial metabolite. Subsequent intracellular reduction of the disulfide bond between linker and DM4 generates the free thiol species, which is then converted to S-methyl DM4 by cellular methyl transferase activity. We provide evidence to suggest that generation of S-methyl DM4 in tumor cells may contribute to in vivo tumor eradication via bystander killing of neighboring tumor cells. Furthermore, we show that S-methyl DM4 is converted to the sulfoxide and sulfone derivatives in the liver, suggesting that hepatic catabolism of the payload to less cytotoxic maytansinoid species contributes to the overall therapeutic window of SAR3419. This compound is currently in phase II clinical evaluation for the treatment of diffuse large B cell lymphoma.

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