To determine the effect of high molecular weight hyaluronic acid (HA) on matrix metalloproteinase 13 (MMP13) expression induced by tumor necrosis factor α (TNF-α) in chondrocytes. Human chondrocytic C28/I2 cells were incubated with TNF-α and HA. In some experiments, the cells were pre-incubated with a CD44 function-blocking monoclonal antibody (CD44 mAb) prior to addition of TNF-α and HA. The expression of MMP13 was determined by real-time reverse-transcription polymerase chain reaction (RT-PCR) and an enzyme linked immunosorbent assay, while the phosphorylation of signaling molecules was measured by western blot analysis. The transcriptional activity of activator protein 1 (AP-1) was analyzed by a reporter assay. To further clarify the molecular mechanisms of HA in MMP13 regulation, the expression level of dual-specificity protein phosphatase 10 (DUSP10)/mitogen-activated protein kinases phosphatase 5 (MKP5) in HA-treated chondrocytes was assessed by real-time RT-PCR, western blotting, and immunofluorescence microscopy. HA decreased MMP13 mRNA and protein expression induced by TNF-α. Blockage of HA-CD44 binding by CD44 mAb suppressed HA-mediated inhibition of MMP13. HA inhibited transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun NH2 -terminal kinase (JNK) induced by TNF-α. Reporter assay findings also revealed that pre-treatment with HA inhibited the transcriptional activity of AP-1 mediated by TNF-α. Moreover, HA induced the expression of DUSP10/MKP5, a negative regulator of p38 MAPK and JNK pathways. These results indicate that HA-CD44 interactions down-regulate TNF-α-induced MMP13 expression via regulation of DUSP10/MKP5, suggesting that HA plays an important role as a regulatory factor in cartilage degradation. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

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Monitoring of anti-drug antibodies (ADAbs) or serum concentrations of biologicals in treatment of rheumatoid arthritis could provide an explanation for a loss of efficacy and help in the choice of subsequent medication. Current clinical practices do not generally include such monitoring of tumor necrosis factor (TNF)-α blockers on a routine basis. The main aims of this study were to estimate the probabilities of optimal and nonoptimal treatment decisions if infliximab or adalimumab drug trough level (DL) and ADAbs are tested or not in rheumatoid arthritis, and to model cost-effectiveness of performing such monitoring on a routine basis. Data on DLs and ADAbs concentrations were obtained in Finland from clinically requested monitoring analyses of 486 and 1,137 samples from patients on adalimumab and infliximab, respectively. DL was within the target range in 42% of samples from adalimumab- and 50.4% of infliximab-treated patients. ADAbs were detected in approximately 20% and 13.5% of samples from adalimumab- and infliximab-treated patients, respectively. ADAbs were found in 52.3% and 41.3% of those with low adalimumab or infliximab DLs, respectively. The monitoring data were incorporated into probabilities for making the optimal treatment decision. Economic impact of clinical decision-making was modeled in a short-term (3-6 months) scenario with 100 hypothetical patients. In the model, the combined measurement of DLs and ADAbs was cost-saving compared to the nontesting scenario when the monitoring results affected the treatment decision in at least 2-5 of 100 patients, a proportion which is easily exceeded in real-life clinical practice. This study indicates that routine monitoring of drug level and ADAbs is cost-beneficial in clinical practice, thereby improving the decision-making process in using TNF-α blockers.

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On April 22, 2016 Adaptimmune Therapeutics plc (NASDAQ:ADAP), a leader in the use of TCR engineered T-cell therapy to treat cancer, reported that the company has adopted the name SPEAR T-cells (Specific Peptide Enhanced Affinity Receptor T-cells) to describe its proprietary technology (Press release, Adaptimmune, APR 22, 2016, View Source;p=RssLanding&cat=news&id=2159628 [SID:1234511273]).

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The SPEAR T-cells brand is intended to symbolize the vital role that Adaptimmune’s enhanced affinity T-cell receptors play in targeting cancer.

Adaptimmune has a history of scientific leadership in the field of T-cell engineering and the company’s proprietary T-cell engineering platform, developed over the last 15 years, has generated a strong pipeline of T-cell therapies.

"Affinity optimized T-cell receptors are essential to the fight against cancer," said James Noble, Adaptimmune’s Chief Executive Officer. "Our SPEAR T-cell technology is unique in delivering correctly identified targets and enhanced affinity TCRs that have the potency needed to attack tumors, but also the optimum specificity to minimize risks of cross-reactivity. Our proprietary technology provides us with ‘supra-natural’ TCRs that enable the acceleration of our programs and also facilitates our development of second generation TCRs."

On April 22, 2016 Adaptimmune Therapeutics plc (NASDAQ:ADAP), a leader in the use of TCR engineered T-cell therapy to treat cancer, reported that they have hosted an Investor and Analyst meeting in New York and presented clinical and corporate updates that included progress with pipeline development and manufacturing process optimization (Press release, Adaptimmune, APR 22, 2016, View Source;p=RssLanding&cat=news&id=2159734 [SID:1234511272]).

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"At today’s event, we were delighted to present an overview of our T-cell therapy and Adaptimmune’s position within the exciting immune-oncology field," said James Noble, Chief Executive Officer. "We also reported on our upcoming goals and took the opportunity to announce MAGE-A4 as the company’s next target with the objective of achieving IND acceptance in 2017."

The presentations included updates on the company’s synovial sarcoma and multiple myeloma studies, as well as on progress with optimization of manufacturing processes and the construction of a dedicated manufacturing plant in Philadelphia scheduled to open in 2017.

Adaptimmune also announced the establishment of its scientific advisory board, to be chaired by cancer immunotherapy expert, Crystal Mackall, M.D., Professor of Pediatrics and Medicine and Associate Director of the Stanford Cancer Institute, and the adoption of the name SPEAR T-cells (Specific Peptide Enhanced Affinity Receptor T-cells) to describe its proprietary technology.

In addition to James Noble, CEO, the presenters were:

Helen Tayton-Martin Ph.D., MBA, Chief Operating Officer, Adaptimmune
Bent Jakobsen, Ph.D., Scientific Founder, Adaptimmune
Stephan Grupp, M.D., Ph.D, Novotny Professor of Pediatrics, University of Pennsylvania Perelman School of Medicine
Aaron Rapoport, M.D., Professor of Medicine, Gary Jobson Professor in Medical Oncology, University of Maryland Marlene and Stewart Greenebaum Cancer Center
Rafael Amado, M.D., Chief Medical Officer, Adaptimmune
Gwendolyn Binder-Scholl, Ph.D., Chief Technology Officer, Adaptimmune
A summary of clinical and corporate highlights presented at the Investor and Analyst Day is set out below. The slide presentation and a replay of the webcast from the event will be available on the company’s website for 30 days following the event at ir.adaptimmune.com.

Clinical and corporate highlights through April 2016:

Proprietary SPEAR T-cell technology that uniquely delivers:
Correctly identified targets
Specificity and optimal affinity TCRs
‘Supra-natural’ TCRs to accelerate programs
Enhanced effectiveness of TCRs: Generation 2 and 3
Multiple clinical responses in synovial sarcoma, a solid tumor
New images presented showing resolution of large solid lesions
Cohort 2 suggests responses in low expressers
Cohort 3 suggests importance of fludarabine
Cohort 4 starting shortly

Over 90% response rate in multiple myeloma study in conjunction with ASCT
Median overall survival of ~3 years (as of January 2016)
Pivotal studies in sarcoma to start in 4Q16/1Q17
Company INDs open for NY-ESO, MAGE-A10 and AFP
Next IND in 2017: MAGE-A4
Generation 2 INDs from 2017

These TCRs all derive from Adaptimmune’s proprietary technology
Active programs give broad coverage of tumors

Milestones met through April 2016
Expanded into autoimmune
Expanded strategic immunotherapy collaboration with GSK
Secured NY-ESO breakthrough therapy designation in synovial sarcoma
Secured NY-ESO orphan drug designation
IND opened for AFP in hepatocellular cancer

Manufacturing processes optimized
Proprietary T-cell expansion method
Commercial-ready process in place
EU and US contract manufacturers in place

Progressed construction of a dedicated manufacturing plant in Philadelphia
Manufacturing plant scheduled to open in 2017
Potential to enable treatment of up to 1,200 patients per year

Financial position confirmed
Total liquidity position of $248 million as of December 31, 2015
Current capital can fund the business through mid-2018

Cathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models.
Validation of cathepsin S selectivity was carried out by assaying fluorogenic substrate turnover using recombinant cathepsin protease. Complete kinetic analysis was carried out and true K i values calculated. Abrogation of tumour invasion using murine MC38 and human MCF7 cell lines were carried out in vitro using a transwell migration assay. Effect on endothelial tube formation was evaluated using primary HUVEC cells. The effect of inhibitor in vivo on MC38 and MCF7 tumor progression was evaluated using cells propagated in C57BL/6 and BALB/c mice respectively. Subsequent immunohistochemical staining of proliferation (Ki67) and apoptosis (TUNEL) was carried out on MCF7 tumors.
We confirmed that this inhibitor was able to selectively target cathepsin S over family members K, V, L and B. The inhibitor also significantly reduced MC38 and MCF7 cell invasion and furthermore, significantly reduced HUVEC endothelial tubule formation in vitro. In vivo analysis revealed that the compound could significantly reduce tumor volume in murine MC38 syngeneic and MCF7 xenograft models. Immunohistochemical analysis of MCF7 tumors revealed cathepsin S inhibitor treatment significantly reduced proliferation and increased apoptosis.
In summary, these results highlight the characterisation of this nitrile cathepsin S inhibitor using in vitro and in vivo tumor models, presenting a compound which may be used to further dissect the role of cathepsin S in cancer progression and may hold therapeutic potential.

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