Current Issue : July - September Volume : 2017 Issue Number : 3 Articles : 5 Articles
Antibody-drug conjugates (ADCs) have recently emerged as efficient and selective cancer\ntreatment therapeutics. Currently, alternative forms of drug carriers that can replace monoclonal\nantibodies are under intensive investigation. Here, a cytotoxic conjugate of an anti-HER2 (Human\nEpidermal Growth Factor Receptor 2) diaffibody with monomethyl-auristatin E (MMAE) is proposed\nas a potential anticancer therapeutic. The anti-HER2 diaffibody was based on the ZHER2:4 affibody\namino acid sequence. The anti-HER2 diaffibody has been expressed as a His-tagged protein in\nE. coli and purified by Ni-nitrilotriacetyl (Ni-NTA) agarose chromatography. The molecule was\nproperly folded, and the high affinity and specificity of its interaction with HER2 was confirmed\nby surface plasmon resonance (SPR) and flow cytometry, respectively. The (ZHER2:4)2DCS-MMAE\nconjugate was obtained by coupling the maleimide group linked with MMAE to cysteines, which\nwere introduced in a drug conjugation sequence (DCS). Cytotoxicity of the conjugate was evaluated\nusing the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide MTT assay and the\nxCELLigence Real-Time Cell Analyzer. Our experiments demonstrated that the conjugate delivered\nauristatin E specifically to HER2-positive tumor cells, which finally led to their death. These results\nindicate that the cytotoxic diaffibody conjugate is a highly potent molecule for the treatment of\nvarious types of cancer overexpressing HER2 receptors....
Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression\nand metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly\nelucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue\ncompared with that of normal lung tissue, and high VCAM-1 expression correlated with poor survival\nin lung cancer patients. VCAM-1 knockdown reduced migration of A549 human lung cancer cells\ninto Matrigel, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1\n(VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1 mediated A549\ncell migration into Matrigel. Next, we developed a human monoclonal antibody specific to human\nand mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody\nlibrary using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar\naffinity for VCAM-1-D6 and that it potently suppressed the migration of A549 and NCI-H1299 lung\ncancer cell lines into Matrigel. Taken together, these results suggest that VCAM-1-D6 is a key domain\nfor regulating VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6\nhuMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion....
Background. It is urgent for patients with hepatitis C virus (HCV) infection to find a safe, effective, and interferon-free regimen\nto optimize therapy. A comprehensive analysis was performed to evaluate the efficacy and safety of the grazoprevir combined\nwith elbasvir, with or without ribavirin (RBV), in 777 treatment-naive and treatment-experienced patients with HCV genotype\n1 infection from 3 randomized controlled trials (RCTs). Method. We collected data from the following trials: C-WORTHY\n(NCT01717326), C-SALVAGE (NCT02105454), and C-EDGE (NCT02105467). All patients received grazoprevir plus elbasvir with\nor withoutRBVfor 12 or 18weeks.The sustained virological response (SVR) 12weeks after end of treatment was calculated for overall\nand subgroups. Results. 568 (73%) patients were treatment-naive. Overall, 95% (95% CI: 93ââ?¬â??96) patients achieved SVR12, 95%\n(95% CI: 92ââ?¬â??96) for treatment-naive and 96% (95% CI: 92ââ?¬â??98) for previously treated patients, respectively. Treatment duration and\ntreatment regimen did not have great difference in SVR12 rates. The most common AEs were fatigue (18%ââ?¬â??29%), headache (20%),\nnausea (8%ââ?¬â??14%), and asthenia (4%ââ?¬â??12%). One patient (<1%) receiving grazoprevir plus elbasvir alone and one (<1%) receiving\ngrazoprevir plus elbasvir plus RBV had treatment-related serious AEs. Conclusions.The result shows that 12-week grazoprevir plus\nelbasvir therapy is safe and effective for treatment-naive patients with HCV genotype 1....
Intense efforts have been made by both industry and academia over the last three\ndecades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as ââ?¬Å?blood\nsubstitutesââ?¬Â. Human trials conducted so far by several manufactures in a variety of clinical indications,\nincluding trauma, and elective surgeries have failed and no product has gained the Food and Drug\nAdministration approval for human use. Safety concerns due to frequent incidences of hemodynamic,\ncardiac events, and even death led to the termination of some of these trials. Several second generation\nHBOC products that have been chemically and/or genetically modified (or in some cases ligated\nwith carbon monoxide (CO)) found a new clinical application in conditions as complex as sickle\ncell disease (SCD). By virtue of higher oxygen affinity (P50) (R-state), and smaller size, HBOCs may\nbe able to reach the microvasculature unload of oxygen to reverse the cycles of sickling/unsickling\nof the deoxy-sickle cell Hb (HbS) (T-state), thus preventing vaso-occlusion, a central event in SCD\npathophysiology. However, biochemically, it is thought that outside the red blood cell (due to frequent\nhemolysis), free HbS or infused HBOCs are capable of interfering with a number of oxidative and\nsignaling pathways and may, thus, negate any benefit that HBOCs may provide. This review discusses\nthe advantages and disadvantages of using HBOCs in SCD....
HS628 has been developed as a proposed biosimilar product of originator tocilizumab (Actemra). An extensive physicochemical\nand biological characterization was conducted to assess similarity between HS628 and originator tocilizumab. The amino\nacid sequence was shown to be identical between HS628 and originator tocilizumab. The higher order structure was found\nto be indistinguishable from originator tocilizumab. Concerning purity and heterogeneity, HS628 was demonstrated to have\nsimilar posttranslational modifications, charge heterogeneity, size heterogeneity, and glycosylation to originator tocilizumab.\nMoreover, HS628 exhibited highly similar binding affinity and antiproliferative activity as well as capability of inhibiting STAT3\nphosphorylation compared to originator tocilizumab. Taken together, HS628 can be considered as a highly similar molecule to\noriginator tocilizumab in terms of physicochemical and biological properties....
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