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Search results for: Anti AVP Monoclonal

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#28131992   2017/01/28 To Up

The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion.

Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion.
Chunwan Lu, Amy V Paschall, Huidong Shi, Natasha Savage, Jennifer L Waller, Maria E Sabbatini, Nicholas H Oberlies, Cedric Pearce, Kebin Liu

1891 related Products with: The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion.



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#24733473   2014/04/14 To Up

Efficacy and safety of AVP-21D9, an anthrax monoclonal antibody, in animal models and humans.

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Timely administration of antibiotics approved for the treatment of anthrax disease may prevent associated morbidity and mortality. However, any delay in initiating antimicrobial therapy may result in increased mortality, as inhalational anthrax progresses rapidly to the toxemic phase of disease. An anthrax antitoxin, AVP-21D9, also known as Thravixa (fully human anthrax monoclonal antibody), is being developed as a therapeutic agent against anthrax toxemia. The efficacy of AVP-21D9 in B. anthracis-infected New Zealand White rabbits and in cynomolgus macaques was evaluated, and its safety and pharmacokinetics were assessed in healthy human volunteers. The estimated mean elimination half-life values of AVP-21D9 in surviving anthrax-challenged rabbits and nonhuman primates (NHPs) ranged from approximately 2 to 4 days and 6 to 11 days, respectively. In healthy humans, the mean elimination half-life was in the range of 20 to 27 days. Dose proportionality was observed for the maximum serum concentration (Cmax) of AVP-21D9 and the area under the concentration-time curve (AUC). In therapeutic efficacy animal models, treatment with AVP-21D9 resulted in survival of up to 92% of the rabbits and up to 67% of the macaques. Single infusions of AVP-21D9 were well tolerated in healthy adult volunteers across all doses evaluated, and no serious adverse events were reported. (This study has been registered at ClinicalTrials.gov under registration no. NCT01202695.).
Nina V Malkevich, Robert J Hopkins, Edward Bernton, Gabriel T Meister, Eric M Vela, George Atiee, Virginia Johnson, Gary S Nabors, Ronald T Aimes, Boris Ionin, Mario H Skiadopoulos

2313 related Products with: Efficacy and safety of AVP-21D9, an anthrax monoclonal antibody, in animal models and humans.

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#17951532   // To Up

Pituitary adenylate cyclase-activating polypeptide stimulates corticotropin-releasing factor, vasopressin and interleukin-6 gene transcription in hypothalamic 4B cells.

Corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) are the two major regulatory peptides in the hypothalamic-pituitary-adrenal axis. CRF, produced in the hypothalamic paraventricular nucleus (PVN) in response to stress, is secreted into the pituitary portal circulation, resulting in the release of adrenocorticotropic hormone from the anterior pituitary. AVP is synthesized in the PVN and supraoptic nucleus by various stressors. Hypothalamic 4B cells coexpress CRF and AVP. In 4B cells transfected with either a CRF or an AVP promoter-luciferase construct, forskolin increased the transcriptional activity of CRF or AVP. In the present study, we tried to determine whether pituitary adenylate cyclase-activating polypeptide (PACAP) regulates both CRF and AVP genes in the hypothalamic cells, because receptors for PACAP were expressed in the hypothalamic cells. PACAP stimulated activity of both CRF and AVP promoter via protein kinase A pathway. PACAP stimulated interleukin (IL)-6 promoter activity and the levels of IL-6 mRNA and protein. IL-6 stimulated activity of both CRF and AVP promoter in a dose-dependent manner. Finally, we found that the stimulatory effects of PACAP on both activities were significantly inhibited by treatment with anti-IL-6 monoclonal antibody. These data suggest that PACAP is involved in regulating the synthesis of IL-6 mRNA and IL-6 protein, and that the increase in endogenous IL-6 also contributes to stimulate the expression of both CRF and AVP genes. Taken together, these findings indicate that PACAP stimulates the transcription of CRF, AVP, and IL-6 genes in hypothalamic 4B cells.
Kazunori Kageyama, Komaki Hanada, Yasumasa Iwasaki, Satoru Sakihara, Takeshi Nigawara, John Kasckow, Toshihiro Suda

2038 related Products with: Pituitary adenylate cyclase-activating polypeptide stimulates corticotropin-releasing factor, vasopressin and interleukin-6 gene transcription in hypothalamic 4B cells.

96T5 x 50 ug1 mg200ug50 ug200ug1 mg200ug96 wells (1 kit)200ug10 ug100

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#17452469   2007/04/23 To Up

Human monoclonal antibody AVP-21D9 to protective antigen reduces dissemination of the Bacillus anthracis Ames strain from the lungs in a rabbit model.

Dutch-belted and New Zealand White rabbits were passively immunized with AVP-21D9, a human monoclonal antibody to protective antigen (PA), at the time of Bacillus anthracis spore challenge using either nasal instillation or aerosol challenge techniques. AVP-21D9 (10 mg/kg) completely protected both rabbit strains against lethal infection with Bacillus anthracis Ames spores, regardless of the inoculation method. Further, all but one of the passively immunized animals (23/24) were completely resistant to rechallenge with spores by either respiratory challenge method at 5 weeks after primary challenge. Analysis of the sera at 5 weeks after primary challenge showed that residual human anti-PA levels decreased by 85 to 95%, but low titers of rabbit-specific anti-PA titers were also measured. Both sources of anti-PA could have contributed to protection from rechallenge. In a subsequent study, bacteriological and histopathology analyses revealed that B. anthracis disseminated to the bloodstream in some naïve animals as early as 24 h postchallenge and increased in frequency with time. AVP-21D9 significantly reduced the dissemination of the bacteria to the bloodstream and to various organs following infection. Examination of tissue sections from infected control animals, stained with hematoxylin-eosin and the Gram stain, showed edema and/or hemorrhage in the lungs and the presence of bacteria in mediastinal lymph nodes, with necrosis and inflammation. Tissue sections from infected rabbits dosed with AVP-21D9 appeared comparable to corresponding tissues from uninfected animals despite lethal challenge with B. anthracis Ames spores. Concomitant treatment with AVP-21D9 at the time of challenge conferred complete protection in the rabbit inhalation anthrax model. Early treatment increased the efficacy progressively and in a dose-dependent manner. Thus, AVP-21D9 could offer an adjunct or alternative clinical treatment regimen against inhalation anthrax.
Johnny W Peterson, Jason E Comer, Wallace B Baze, David M Noffsinger, Autumn Wenglikowski, Kristin G Walberg, Jason Hardcastle, Jennifer Pawlik, Kathryn Bush, Joanna Taormina, Scott Moen, John Thomas, Bagram M Chatuev, Laurie Sower, Ashok K Chopra, Lawrence R Stanberry, Ritsuko Sawada, Wolfgang W Scholz, Jagadish Sircar

1875 related Products with: Human monoclonal antibody AVP-21D9 to protective antigen reduces dissemination of the Bacillus anthracis Ames strain from the lungs in a rabbit model.

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#16428748   // To Up

Human monoclonal anti-protective antigen antibody completely protects rabbits and is synergistic with ciprofloxacin in protecting mice and guinea pigs against inhalation anthrax.

Prevention of inhalation anthrax requires early and extended antibiotic therapy, and therefore, alternative treatment strategies are needed. We investigated whether a human monoclonal antibody (AVP-21D9) to protective antigen (PA) would protect mice, guinea pigs, and rabbits against anthrax. Control animals challenged with Bacillus anthracis Ames spores by the intranasal route died within 3 to 7 days. AVP-21D9 alone provided minimal protection against anthrax in the murine model, but its efficacy was notably better in guinea pigs. When Swiss-Webster mice, challenged with five 50% lethal doses (LD50s) of anthrax spores, were given a single 16.7-mg/kg of body weight AVP-21D9 antibody dose combined with ciprofloxacin (30 mg/kg/day for 6 days) 24 h after challenge, 100% of the mice were protected for more than 30 days, while ciprofloxacin or AVP-21D9 alone showed minimal protection. Similarly, when AVP-21D9 antibody (10 to 50 mg/kg) was combined with a low, nonprotective dose of ciprofloxacin (3.7 mg/kg/day) and administered to guinea pigs for 6 days, synergistic protection against anthrax was observed. In contrast, a single dose of AVP-21D9 antibody (1, 5, 10, or 20 mg/kg) but not 0.2 mg/kg alone completely protected rabbits against challenge with 100 LD50s of B. anthracis Ames spores, and 100% of the rabbits survived rechallenge. Further, administration of AVP-21D9 (10 mg/kg) to rabbits at 0, 6, and 12 h after challenge with anthrax spores resulted in 100% survival; however, delay of antibody treatment by 24 and 48 h reduced survival to 80% and 60%, respectively. Serological analysis of sera from various surviving animals 30 days postprimary infection showed development of a species-specific PA enzyme-linked immunosorbent assay antibody titer that correlated with protection against reinfection. Taken together, the effectiveness of human anti-PA antibody alone or in combination with low ciprofloxacin levels may provide the basis for an improved strategy for prophylaxis or treatment following inhalation anthrax infection.
Johnny W Peterson, Jason E Comer, David M Noffsinger, Autumn Wenglikowski, Kristin G Walberg, Bagram M Chatuev, Ashok K Chopra, Lawrence R Stanberry, Angray S Kang, Wolfgang W Scholz, Jagadish Sircar

1027 related Products with: Human monoclonal anti-protective antigen antibody completely protects rabbits and is synergistic with ciprofloxacin in protecting mice and guinea pigs against inhalation anthrax.

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#16331351   2005/12/06 To Up

Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies.

The arginine vasopressin (AVP) gene is expressed in certain cancers such as breast cancer, where it is believed to act as an autocrine growth factor. However, little is known about the regulation of the AVP protein precursor (proAVP) or AVP-mediated signaling in breast cancer and this study was undertaken to address some of the basic issues. The cultured cell lines examined (Mcf7, Skbr3, BT474, ZR75, Mcf10a) and human breast cancer tissue extract were found to express proAVP mRNA. Western analysis revealed multiple forms of proAVP protein were present in cell lysates, corresponding to those detected in human hypothalamus extracts. Monoclonal antibodies directed against different regions of proAVP bound to intact live Mcf7 and Skbr3 cells. Dexamethasone increased the amount of proAVP-associated glycopeptide (VAG) secreted by Skbr3 cells and a combination of dexamethasone, IBMX and 8br-cAMP increased cellular levels of VAG. Exogenous AVP (1, 10, and 100 nM) elevated phospho-ERK1/2 levels, and increased cell proliferation was observed in the presence of 10 nM AVP. Concurrent treatment with the V1a receptor antagonist SR49059 reduced the effects of AVP on proliferation in Mcf7 cells, and abolished it in Skbr3 cells. Results here show that proAVP components are found at the surface of Skbr3 and Mcf7 cells and are also secreted from these cells. In addition, they show that AVP promotes cancer cell growth, apparently through a V1-type receptor-mediated pathway and subsequent ERK1/2 activation. Thus, strategies for targeting proAVP should be examined for their effectiveness in diagnosing and treating breast cancer.
Brendan P Keegan, Bonnie L Akerman, Christel Péqueux, William G North

2876 related Products with: Provasopressin expression by breast cancer cells: implications for growth and novel treatment strategies.

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#15925272   2005/04/22 To Up

The detection of protective antigen (PA) associated with spores of Bacillus anthracis and the effects of anti-PA antibodies on spore germination and macrophage interactions.

The protective antigen (PA) component of the anthrax toxins is an essential virulence factor of Bacillus anthracis and is the major protective immunogen. The kinetics of PA production during growth of B. anthracis, and the roles of anti-PA antibody in host immunity are not clearly defined. Production of PA by the vegetative organisms peaks during the shift from exponential to stationary phase of growth. Recently, PA was also found to be associated with spores. In our study, PA-specific mRNA was detected in spores by RT-PCR within 15-min of exposure to germinant. PA protein was detected by immunomagnetic electrochemiluminescence (ECL) on spores within 1 h of exposure to a germination medium and was rapidly released into the supernatant. PA was not demonstrated on ungerminated spores by RNA analysis, ECL, or spore-based anti-PA ELISA; however, it was detected on ungerminated spores by immunoelectron microscopy (immunoem). In rabbits, PA induces polyclonal antibodies (Abs) that, in addition to their anti-toxin neutralizing activities, exhibit anti-spore activities. In this study, the anti-spore effects of a human monoclonal Ab specific for PA (AVP-hPA mAb, Avanir Pharmaceuticals) were characterized. AVP-hPA mAb retarded germination in vitro, and enhanced the phagocytic and sporicidal activities of macrophages. The activities were comparable to those of the polyclonal rabbit anti-rPA Ab. Assays to detect germination inhibitory activity (GIA) in serum from vaccinated mice and guinea pigs suggested a possible role for anti-PA Abs in protection. Thus, anti-PA Ab-mediated, anti-spore activities may play a role in protection during the early stages of an anthrax infection.
C K Cote, C A Rossi, A S Kang, P R Morrow, J S Lee, S L Welkos

2977 related Products with: The detection of protective antigen (PA) associated with spores of Bacillus anthracis and the effects of anti-PA antibodies on spore germination and macrophage interactions.

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#15671576   // To Up

Human monoclonal antibodies that neutralize anthrax toxin by inhibiting heptamer assembly.

A panel of human anti-anthrax protective antigen IgG1 monoclonal antibodies were evaluated to determine the mechanism of toxin neutralization. AVP-22G12, AVP-1C6 and AVP-21D9 bound to the protective antigen with picomolar affinities to distinct non-overlapping linear epitopes. Two of the antibodies neutralized the anthrax toxin by completely inhibiting the protective antigen oligomer assembly process in vitro.
Fei Wang, Paul Ruther, Ivy Jiang, Ritsuko Sawada-Hirai, Shu Man Sun, Rebecca Nedellec, Phillip R Morrow, Angray S Kang

2923 related Products with: Human monoclonal antibodies that neutralize anthrax toxin by inhibiting heptamer assembly.

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#15140257   2004/05/12 To Up

Human anti-anthrax protective antigen neutralizing monoclonal antibodies derived from donors vaccinated with anthrax vaccine adsorbed.

BACKGROUND: Potent anthrax toxin neutralizing human monoclonal antibodies were generated from peripheral blood lymphocytes obtained from Anthrax Vaccine Adsorbed (AVA) immune donors. The anti-anthrax toxin human monoclonal antibodies were evaluated for neutralization of anthrax lethal toxin in vivo in the Fisher 344 rat bolus toxin challenge model. METHODS: Human peripheral blood lymphocytes from AVA immunized donors were engrafted into severe combined immunodeficient (SCID) mice. Vaccination with anthrax protective antigen and lethal factor produced a significant increase in antigen specific human IgG in the mouse serum. The antibody producing lymphocytes were immortalized by hybridoma formation. The genes encoding the protective antibodies were rescued and stable cell lines expressing full-length human immunoglobulin were established. The antibodies were characterized by; (1) surface plasmon resonance; (2) inhibition of toxin in an in vitro mouse macrophage cell line protection assay and (3) in vivo in a Fischer 344 bolus lethal toxin challenge model. RESULTS: The range of antibodies generated were diverse with evidence of extensive hyper mutation, and all were of very high affinity for PA83~1 x 10-10-11M. Moreover all the antibodies were potent inhibitors of anthrax lethal toxin in vitro. A single IV dose of AVP-21D9 or AVP-22G12 was found to confer full protection with as little as 0.5x (AVP-21D9) and 1x (AVP-22G12) molar equivalence relative to the anthrax toxin in the rat challenge prophylaxis model. CONCLUSION: Here we describe a powerful technology to capture the recall antibody response to AVA vaccination and provide detailed molecular characterization of the protective human monoclonal antibodies. AVP-21D9, AVP-22G12 and AVP-1C6 protect rats from anthrax lethal toxin at low dose. Aglycosylated versions of the most potent antibodies are also protective in vivo, suggesting that lethal toxin neutralization is not Fc effector mediated. The protective effect of AVP-21D9 persists for at least one week in rats. These potent fully human anti-PA toxin-neutralizing antibodies are attractive candidates for prophylaxis and/or treatment against Anthrax Class A bioterrorism toxins.
Ritsuko Sawada-Hirai, Ivy Jiang, Fei Wang, Shu Man Sun, Rebecca Nedellec, Paul Ruther, Alejandro Alvarez, Diane Millis, Phillip R Morrow, Angray S Kang

1643 related Products with: Human anti-anthrax protective antigen neutralizing monoclonal antibodies derived from donors vaccinated with anthrax vaccine adsorbed.

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#11324526   // To Up

[Effect of AVP(4-8) administration on Ca2+/CaM-dependent protein kinase II autophosphorylation in rat brain].

The extent increase of Ca2+/CaM-dependent protein kinase II (CaMK II) autophosphorylation in various brain regions of rat reached a maximum value, one hour after s.c. administration of AVP(4-8). The increase in the cortex amounted to 192% of the control (P < 0.001), while in the hippocampus only 40% (P < 0.05). The autophosphorylation of CaMK II was dependent on both Ca2+ and CaM. Western blotting with anti-CaMK II alpha monoclonal antibody showed that the content of CaMK II alpha in cortex did not show detectable change in 1 h as compared to the control group. ZDC(C)PR, an antagonist of AVP(4-8), markedly blocked the effect of AVP(4-8), suggesting that AVP (4-8) stimulated CaMK II autophosphorylation is mediated through its receptor.
L Y Qiao, X F Chen, B X Gu, T X Wang, Y C Du

2478 related Products with: [Effect of AVP(4-8) administration on Ca2+/CaM-dependent protein kinase II autophosphorylation in rat brain].

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