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排序方式: 共有85条查询结果,搜索用时 15 毫秒
41.
Matthew J. Bernett Seung Y. Chu Irene Leung Gregory L. Moore Sung-Hyung Lee Erik Pong Hsing Chen Sheryl Phung Umesh S. Muchhal Holly M. Horton Greg A. Lazar John R Desjarlais David E. Szymkowski 《MABS-AUSTIN》2013,5(3):384-396
The CTLA4-Ig fusion proteins abatacept and belatacept are clinically proven immunosuppressants used for rheumatoid arthritis and renal transplant, respectively. Given that both biologics are typically administered chronically by infusion, a need exists for a next-generation CTLA4-Ig with more convenient dosing. We used structure-based protein engineering to optimize the affinity of existing CTLA4-Ig therapeutics for the ligands CD80 and CD86, and for the neonatal Fc receptor, FcRn. From a rationally designed library, we identified four substitutions that enhanced binding to human CD80 and CD86. Coupled with two IgG1 Fc substitutions that enhanced binding to human FcRn, these changes comprise the novel CTLA4-Ig fusion protein, XPro9523. Compared with abatacept, XPro9523 demonstrated 5.9-fold, 23-fold, and 12-fold increased binding to CD80, CD86, and FcRn, respectively; compared with belatacept, CD80, CD86, and FcRn binding increased 1.5-fold, 7.7-fold, and 11-fold, respectively. XPro9523 and belatacept suppressed human T cell proliferation and IL-2 production more potently than abatacept. XPro9523 also suppressed inflammation in the mouse collagen-induced arthritis model. In cynomolgus monkeys, XPro9523 saturated CD80 and CD86 more effectively than abatacept and belatacept, potently inhibited IgM and IgG immunization responses, and demonstrated longer half-life. Pharmacokinetic modeling of its increased potency and persistence suggests that, in humans, XPro9523 may demonstrate superior efficacy and dosing convenience compared with abatacept and belatacept. 相似文献
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Hormonally regulated programmed cell death in barley aleurone cells 总被引:13,自引:0,他引:13
Cell death was studied in barley (cv Himalaya) aleurone cells treated with abscisic acid and gibberellin. Aleurone protoplasts incubated in abscisic acid remained viable in culture for at least 3 weeks, but exposure to gibberellin initiated a series of events that resulted in death. Between 4 and 8 days after incubation in gibberellin, >70% of all protoplasts died. Death, which occurred after cells became highly vacuolated, was manifest by an abrupt loss of plasma membrane integrity followed by rapid shrinkage of the cell corpse. Hydrolysis of DNA began before death and occurred as protoplasts ceased production of alpha-amylase. DNA degradation did not result in the accumulation of discrete low molecular weight fragments. DNA degradation and cell death were prevented by LY83583, an inhibitor of gibberellin signaling in barley aleurone. We conclude that cell death in aleurone cells is hormonally regulated and is the final step of a developmental program that promotes successful seedling establishment. 相似文献
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alpha 1-Proteinase inhibitors (alpha 1-PIs) are members of the serpin
superfamily of proteinase inhibitors, and are important in the maintenance
of homeostasis in a wide variety of animal taxa. Previous studies have
shown that in mice (genus Mus), evolution of alpha 1-PIs is characterized
by gene amplification, region-specific concerted evolution, and rapid
accumulation of amino acid substitutions. The latter occurs primarily in
the reactive center, which is the region of the alpha 1-PI molecule that
determines the inhibitor's specificity for target proteinases. The P1
residue within the reactive center, which is methionine in so-called
orthodox alpha 1-PIs and an amino acid other than methionine in unorthodox
alpha 1-PIs, is a primary determinant of inhibitor specificity. In the
present study, we find that the expression of mRNAs encoding unorthodox
alpha 1-PIs is polymorphic within Mus species, i.e., among individuals or
inbred strains. This is in striking contrast to mRNAs that encode orthodox
alpha 1-PIs, whose concentrations are relatively invariant. The
intraspecies variations in mRNA expression represent polymorphisms in the
structure of the alpha 1- PI gene family. The results, taken together with
previously described aspects of alpha 1-PI evolution, indicate that the
dissimilar levels of polymorphism exhibited by orthodox and unorthodox
alpha 1-PIs, which likely have distinct physiological functions, may
reflect different levels of selective constraint. The significance of this
finding to the evolution of gene families is discussed.
相似文献
46.
Song G Lazar GA Kortemme T Shimaoka M Desjarlais JR Baker D Springer TA 《The Journal of biological chemistry》2006,281(8):5042-5049
The interaction between integrin lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) is critical in immunological and inflammatory reactions but, like other adhesive interactions, is of low affinity. Here, multiple rational design methods were used to engineer ICAM-1 mutants with enhanced affinity for LFA-1. Five amino acid substitutions 1) enhance the hydrophobicity and packing of residues surrounding Glu-34 of ICAM-1, which coordinates to a Mg2+ in the LFA-1 I domain, and 2) alter associations at the edges of the binding interface. The affinity of the most improved ICAM-1 mutant for intermediate- and high-affinity LFA-1 I domains was increased by 19-fold and 22-fold, respectively, relative to wild type. Moreover, potency was similarly enhanced for inhibition of LFA-1-dependent ligand binding and cell adhesion. Thus, rational design can be used to engineer novel adhesion molecules with high monomeric affinity; furthermore, the ICAM-1 mutant holds promise for targeting LFA-1-ICAM-1 interaction for biological studies and therapeutic purposes. 相似文献
47.
Meegalla SK Wall MJ Chen J Wilson KJ Ballentine SK Desjarlais RL Schubert C Crysler CS Chen Y Molloy CJ Chaikin MA Manthey CL Player MR Tomczuk BE Illig CR 《Bioorganic & medicinal chemistry letters》2008,18(12):3632-3637
An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions. 相似文献
48.
Antigen/antibody complexes can efficiently target antigen presenting cells to allow stimulation of the cellular immune response. Due to the difficulty of manufacture and their inherent instability complexes have proved inefficient cancer vaccines. However, anti-idiotypic antibodies mimicking antigens have been shown to stimulate both antibody and T cell responses. The latter are due to T cell mimotopes expressed within the complementarity-determining regions (CDRs) of antibodies that are efficiently presented to dendritic cells in vivo. Based on this observation we have designed a DNA vaccine platform called ImmunoBody™, where cytotoxic T lymphocyte (CTL) and helper T cell epitopes replace CDR regions within the framework of a human IgG1 antibody. The ImmunoBody™ expression system has a number of design features which allow for rapid production of a wide range of vaccines. The CDR regions of the heavy and light chain have been engineered to contain unique restriction endonuclease sites, which can be easily opened, and oligonucleotides encoding the T cell epitopes inserted. The variable and constant regions of the ImmunoBody™ are also flanked by restriction sites, which permit easy exchange of other IgG subtypes. Here we show a range of T cell epitopes can be inserted into the ImmunoBody™ vector and upon immunization these T cell epitopes are efficiently processed and presented to stimulate high frequency helper and CTL responses capable of anti-tumor activity.Key words: DNA vaccines, cancer vaccines, melanoma, CTL, helper T cells 相似文献
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A de novo redesign of the WW domain 总被引:7,自引:0,他引:7
Kraemer-Pecore CM Lecomte JT Desjarlais JR 《Protein science : a publication of the Protein Society》2003,12(10):2194-2205
We have used a sequence prediction algorithm and a novel sampling method to design protein sequences for the WW domain, a small beta-sheet motif. The procedure, referred to as SPANS, designs sequences to be compatible with an ensemble of closely related polypeptide backbones, mimicking the inherent flexibility of proteins. Two designed sequences (termed SPANS-WW1 and SPANS-WW2), using only naturally occurring L-amino acids, were selected for study and the corresponding polypeptides were prepared in Escherichia coli. Circular dichroism data suggested that both purified polypeptides adopted secondary structure features related to those of the target without the aid of disulfide bridges or bound cofactors. The structure exhibited by SPANS-WW2 melted cooperatively by raising the temperature of the solution. Further analysis of this polypeptide by proton nuclear magnetic resonance spectroscopy demonstrated that at 5 degrees C, it folds into a structure closely resembling a natural WW domain. This achievement constitutes one of a small number of successful de novo protein designs through fully automated computational methods and highlights the feasibility of including backbone flexibility in the design strategy. 相似文献