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Mischa R. Müller Kenneth Saunders Christopher Grace Macy Jin Nicole Piche-Nicholas John Steven Ronan O’Dwyer Leeying Wu Lam Khetemenee Yulia Vugmeyster Timothy P. Hickling Lioudmila Tchistiakova Stephane Olland Davinder Gill Allan Jensen Caroline J. Barelle 《MABS-AUSTIN》2012,4(6):673-685
Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity. N-terminal and C-terminal molecular fusions of our lead hit in complex with a naïve VNAR domain were expressed, purified and exhibited the retention of high affinity binding to HSA, but also cross-selectivity to mouse, rat and monkey serum albumin both in vitro and in vivo. Furthermore, the naïve VNAR had enhanced pharmacokinetic (PK) characteristics in both N- and C-terminal orientations and when tested as a three domain construct with naïve VNAR flanking the HSA binding domain at both the N and C termini. Molecules derived from this platform technology also demonstrated the potential for clinical utility by being available via the subcutaneous route of delivery. This study thus demonstrates the first in vivo functional efficacy of a VNAR binding domain with the ability to enhance PK properties and support delivery of multifunctional therapies. 相似文献
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Developing core outcome set for vitiligo clinical trials: international e‐Delphi consensus 下载免费PDF全文
Viktoria Eleftheriadou Kim Thomas Nanja van Geel Iltefat Hamzavi Henry Lim Tamio Suzuki Ichiro Katayama Tag Anbar Marwa Abdallah Laïla Benzekri Yvon Gauthier John Harris Caio Cesar Silva de Castro Amit Pandya Boon Kee Goh Cheng‐Che E. Lan Naoki Oiso Ahmed Al Issa Samia Esmat Caroline Le Poole Ai‐Young Lee Davinder Parsad Alain Taieb Mauro Picardo Khaled Ezzedine 《Pigment cell & melanoma research》2015,28(3):363-369
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Oleg V. Kovalenko Andrea Olland Nicole Piché-Nicholas Adarsh Godbole Daniel King Kristine Svenson Valerie Calabro Mischa R. Müller Caroline J. Barelle William Somers Davinder S. Gill Lidia Mosyak Lioudmila Tchistiakova 《The Journal of biological chemistry》2013,288(24):17408-17419
The immunoglobulin new antigen receptors (IgNARs) are a class of Ig-like molecules of the shark immune system that exist as heavy chain-only homodimers and bind antigens by their single domain variable regions (V-NARs). Following shark immunization and/or in vitro selection, V-NARs can be generated as soluble, stable, and specific high affinity monomeric binding proteins of ∼12 kDa. We have previously isolated a V-NAR from an immunized spiny dogfish shark, named E06, that binds specifically and with high affinity to human, mouse, and rat serum albumins. Humanization of E06 was carried out by converting over 60% of non-complementarity-determining region residues to those of a human germ line Vκ1 sequence, DPK9. The resulting huE06 molecules have largely retained the specificity and affinity of antigen binding of the parental V-NAR. Crystal structures of the shark E06 and its humanized variant (huE06 v1.1) in complex with human serum albumin (HSA) were determined at 3- and 2.3-Å resolution, respectively. The huE06 v1.1 molecule retained all but one amino acid residues involved in the binding site for HSA. Structural analysis of these V-NARs has revealed an unusual variable domain-antigen interaction. E06 interacts with HSA in an atypical mode that utilizes extensive framework contacts in addition to complementarity-determining regions that has not been seen previously in V-NARs. On the basis of the structure, the roles of various elements of the molecule are described with respect to antigen binding and V-NAR stability. This information broadens the general understanding of antigen recognition and provides a framework for further design and humanization of shark IgNARs. 相似文献
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Huebner KD Jassal DS Halevy O Pines M Anderson JE 《American journal of physiology. Heart and circulatory physiology》2008,294(4):H1550-H1561
The effect of halofuginone (Halo) on established fibrosis in older mdx dystrophic muscle was investigated. Mice (8 to 9 mo) treated with Halo (or saline in controls) for 5, 10, or 12 wk were assessed weekly for grip strength and voluntary running. Echocardiography was performed at 0, 5, and 10 wk. Respiratory function and exercise-induced muscle damage were tested. Heart, quadriceps, diaphragm, and tibialis anterior muscles were collected to study fibrosis, collagen I and III expression, collagen content using a novel collagenase-digestion method, and cell proliferation. Hepatocyte growth factor and alpha-smooth muscle actin proteins were assayed in quadriceps. Halo decreased fibrosis (diaphragm and quadriceps), collagen I and III expression, collagen protein, and smooth muscle actin content after 10 wk treatment. Muscle-cell proliferation increased at 5 wk, and hepatocyte growth factor increased by 10 wk treatment. Halo markedly improved both cardiac and respiratory function and reduced damage and improved recovery from exercise. The overall impact of established dystrophy and dysfunction in cardiac and skeletal muscles was reduced by Halo treatment. Marked improvements in vital-organ functions implicate Halo as a strong candidate drug to reduce morbidity and mortality in Duchenne muscular dystrophy. 相似文献
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Aesthetic considerations in nasal reconstruction and the role of modified nasal subunits 总被引:7,自引:0,他引:7
In 1985, Burget and Menick's landmark article on the nasal subunit principle popularized the technique of reconstructing the specific topographic subunits that they identified as the dorsum, tip, and columella and the paired alae, sidewalls, and soft triangles. In patients with more than 50 percent of subunit loss, Burget and Menick proposed removing the remaining portion of the subunit and reconstructing the entire subunit with a skin graft or flap. They further supported the placement of incisions for local flaps along borders of aesthetic subunits to maximize scar camouflage. Although the concept of nasal subunits is important in planning the reconstruction, other aesthetic considerations, such as skin texture, color, contour, and actinic damage, are also crucial in achieving an optimal result. Often, focusing on these aspects with the goal of nasal symmetry in mind leads to the violation of the subunit principle but provides a pleasing result of both the defect and the donor site. The purpose of this study was to demonstrate when and how the modification of the nasal subunit principle is used to achieve coverage of nasal skin defects. A retrospective analysis of patients who underwent nasal reconstruction after skin cancer ablation surgery by one surgeon at the Hospital of the University of Pennsylvania from 1987 to 2000 was performed. During this 13-year period, 219 patients underwent 245 nasal reconstructions. Seventy-four patients with 76 reconstructions (31 percent) had procedures that violated the classic nasal subunit principle. Eight of these 74 patients (11 percent) had complications, and eight (11 percent) had 10 revisions performed. The aesthetic and functional results were graded as excellent, good, and fair. The results for the 74 patients who underwent modification of the subunit were excellent in 85 percent, good in 13 percent, and fair in 2 percent. Case reports were selected to illustrate situations in which the nasal subunit was altered. 相似文献
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Henderson EA Bavetsias V Theti DS Wilson SC Clauss R Jackman AL 《Bioorganic & medicinal chemistry》2006,14(14):5020-5042
The alpha-FR has been reported to be overexpressed in many carcinomas, in particular those of the ovary and uterus. The high expression of alpha-FR in some tumours compared with normal tissues has been exploited over the last decade for folate-mediated targeting of macromolecules, anticancer drugs, imaging agents and nucleic acids to cancer cells. CB300638, a cyclopenta[g]quinazoline-based inhibitor of thymidylate synthase (TS), has been reported to have high affinity for the receptor and selectivity for alpha-FR overexpressing tumour cell lines. In this study, the structural features of the molecule, in particular modifications at the 2-position, have been investigated with respect to TS inhibition, affinity for the alpha-FR and reduced folate carrier (RFC) and activity in A431-FBP cells (transfected with human alpha-FR) compared with neo-transfected A431 cells. Compounds 1a,b, 2a,b and 3a,b were synthesised utilising multistep sequences. It was found that the 2-substituent does not affect the affinity for the alpha-FR; however, it greatly affects selectivity for A431-FBP cells, and suggests that there are factors other than TS inhibition and alpha-FR affinity that are important for the activity of these compounds. Compound 2b (2-CH2OH derivative) displayed the highest selectivity for the A431-FBP cells compared with A431 cells. 相似文献
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Hataishi R Rodrigues AC Neilan TG Morgan JG Buys E Shiva S Tambouret R Jassal DS Raher MJ Furutani E Ichinose F Gladwin MT Rosenzweig A Zapol WM Picard MH Bloch KD Scherrer-Crosbie M 《American journal of physiology. Heart and circulatory physiology》2006,291(1):H379-H384
To learn whether nitric oxide (NO) inhalation can decrease myocardial ischemia-reperfusion (I/R) injury, we studied a murine model of myocardial infarction (MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular (LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury. 相似文献
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