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Antigen affinity

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https://www.readbyqxmd.com/read/29774664/the-lupus-associated-fc%C3%AE-riib-i232t-polymorphism-results-in-impairment-in-the-negative-selection-of-low-affinity-germinal-center-b-cells-via-c-abl
#1
Jyun-Pei Jhou, I-Shing Yu, Haw Hwai, Chih-Shan Chen, Pei-Lung Chen, Shiang-Jong Tzeng
OBJECTIVE: FcγRIIB is an essential negative regulator of B cells to block BCR signaling and to trigger c-Abl-dependent apoptosis of B cells. FcγRIIB-deficient mice display splenomegaly with expansion of B cells, leading to lupus. FcγRIIB-I232T is a hypo-functional polymorphism associated with lupus susceptibility in humans, an autoimmune disease linked to diminished deletion of autoreactive B cells. In the context of FcγRIIB-I232T polymorphism, we investigated the role of FcγRIIB in the deletion of low-affinity germinal center (GC) B cells, an important mechanism for preventing autoimmunity...
May 17, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29774024/quantification-of-hla-dm-dependent-major-histocompatibility-complex-of-class-ii-immunopeptidomes-by-the-peptide-landscape-antigenic-epitope-alignment-utility
#2
Miguel Álvaro-Benito, Eliot Morrison, Esam T Abualrous, Benno Kuropka, Christian Freund
The major histocompatibility complex of class II (MHCII) immunopeptidome represents the repertoire of antigenic peptides with the potential to activate CD4+ T cells. An understanding of how the relative abundance of specific antigenic epitopes affects the outcome of T cell responses is an important aspect of adaptive immunity and offers a venue to more rationally tailor T cell activation in the context of disease. Recent advances in mass spectrometric instrumentation, computational power, labeling strategies, and software analysis have enabled an increasing number of stratified studies on HLA ligandomes, in the context of both basic and translational research...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29772250/development-and-validation-of-a-novel-semi-homogenous-clinical-assay-for-quantitation-of-ranibizumab-in-human-serum
#3
John Lowe, Eric Wakshull, Theresa Shek, Anan Chuntharapai, Rebecca Elliott, Jeriza Rusit, Mauricio Maia
Ranibizumab (Lucentis®), a humanized antigen-binding fragment (Fab) monoclonal antibody that blocks VEGF-A activity is currently approved for the treatment of several retinal degenerative diseases. The assessment of drug pharmacokinetics (PK) is essential for evaluating exposure as it relates to drug safety and efficacy. For drugs administered intravitreally, systemic drug levels during the course of clinical studies are typically 100 to 1000-fold lower than those of similar therapeutics dosed intravenously, posing a significant bioanalytical challenge for PK measurements...
May 14, 2018: Journal of Immunological Methods
https://www.readbyqxmd.com/read/29772075/cd6-mabs-differ-in-epitope-kinetics-and-mechanism-of-action
#4
Lee I Garner, Andrew Hartland, Johannes Breuning, Marion H Brown
CD6 is a type I T cell surface receptor which modulates antigen receptor signalling. Its activity is regulated by binding of its membrane proximal domain (domain 3) to a cell surface ligand, CD166. CD6 monoclonal antibodies (mAbs) specific for the membrane distal domain (domain 1) perturb CD6 function including itolizumab (Alzumab™ ) which has reached the clinic for treatment of autoimmune disease. We characterised molecular and functional properties of several CD6 mAbs including itolizumab to define potential mechanisms of action...
May 17, 2018: Immunology
https://www.readbyqxmd.com/read/29771460/targeting-prostate-cancer-prostate-specific-membrane-antigen-based-diagnosis-and-therapy
#5
REVIEW
Till Wüstemann, Uwe Haberkorn, John Babich, Walter Mier
The high incidence rates of prostate cancer (PCa) raise demand for improved therapeutic strategies. Prostate tumors specifically express the prostate-specific membrane antigen (PSMA), a membrane-bound protease. As PSMA is highly overexpressed on malignant prostate tumor cells and as its expression rate correlates with the aggressiveness of the disease, this tumor-associated biomarker provides the possibility to develop new strategies for diagnostics and therapy of PCa. Major advances have been made in PSMA targeting, ranging from immunotherapeutic approaches to therapeutic small molecules...
May 17, 2018: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29769311/tumor-associated-calreticulin-variants-functionally-compromise-the-peptide-loading-complex-and-impair-its-recruitment-of-mhc-i
#6
Najla Arshad, Peter Cresswell
Major histocompatibility complex-I-β2 m dimers (MHC-I) bind peptides derived from intracellular proteins, enabling the immune system to distinguish between normal cells and those expressing pathogen-derived or mutant proteins. The peptides bind to MHC-I in the endoplasmic reticulum (ER), and this binding is facilitated by the peptide-loading complex (PLC), which contains calreticulin (CRT). CRT associates with MHC-I via a conserved glycan present on MHC-I and recruits it to the PLC for peptide binding. Somatic frameshift mutations in CRT (CRT-FS) drive the proliferation of a subset of myeloproliferative neoplasms (MPNs), which are chronic blood tumors...
May 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29767964/a-synthetic-polymer-affinity-ligand-for-bacillus-thuringiensis-bt-cry1ab-ac-protein-the-use-of-biomimicry-based-on-the-bt-protein-insect-receptor-binding-mechanism
#7
Mingming Liu, Rong Huang, Adam C Weisman, Xiaoyang Yu, Shih-Hui Lee, Yalu Chen, Chao Huang, Senhua Hu, Xiuhua Chen, Wenfeng Tan, Fan Liu, Hao Chen, Kenneth J Shea
We report a novel strategy for creating abiotic Bacillus thuringiensis (Bt) protein affinity ligands by biomimicry of the recognition process that takes place between Bt Cry1Ab/Ac proteins and insect receptor cadherin-like Bt-R1 proteins. Guided by this strategy, a library of synthetic polymer nanoparticles (NPs) was prepared and screened for binding to three epitopes 280FRGSAQGIEGS290, 368RRPFNIGINNQQ379 and 436FRSGFSNSSVSIIR449 located in loop α8, loop 2 and loop 3 of domain II of Bt Cry1Ab/Ac proteins. A negatively charged and hydrophilic nanoparticle (NP12) was found to have high affinity to one of the epitopes, 368RRPFNIGINNQQ379...
May 16, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29762030/structure-function-analysis-of-the-extended-conformation-of-a-polyketide-synthase-module
#8
Xiuyuan Li, Natalia Sevillano, Florencia La Greca, Lindsay Deis, Yu-Chen Liu, Marc C Deller, Irimpan I Mathews, Tsutomu Matsui, David E Cane, Charles S Craik, Chaitan Khosla
Catalytic modules of assembly-line polyketide synthases (PKSs) have previously been observed in two very different conformations-an "extended" architecture and an "arch-shaped" architecture-although the catalytic relevance of neither has been directly established. By the use of a fully human naïve antigen-binding fragment (Fab ) library, a high-affinity antibody was identified that bound to the extended conformation of a PKS module, as verified by X-ray crystallography and tandem size-exclusion chromatography-small-angle X-ray scattering (SEC-SAXS)...
May 18, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29760533/cross-specificity-of-protective-human-antibodies-against-klebsiella-pneumoniae-lps-o-antigen
#9
Tim Rollenske, Valeria Szijarto, Jolanta Lukasiewicz, Luis M Guachalla, Katarina Stojkovic, Katharina Hartl, Lukas Stulik, Simone Kocher, Felix Lasitschka, Mohammed Al-Saeedi, Jutta Schröder-Braunstein, Moritz von Frankenberg, Gereon Gaebelein, Peter Hoffmann, Sabrina Klein, Klaus Heeg, Eszter Nagy, Gabor Nagy, Hedda Wardemann
Humoral immune responses to microbial polysaccharide surface antigens can prevent bacterial infection but are typically strain specific and fail to mediate broad protection against different serotypes. Here we describe a panel of affinity-matured monoclonal human antibodies from peripheral blood immunoglobulin M-positive (IgM+ ) and IgA+ memory B cells and clonally related intestinal plasmablasts, directed against the lipopolysaccharide (LPS) O-antigen of Klebsiella pneumoniae, an opportunistic pathogen and major cause of antibiotic-resistant nosocomial infections...
May 14, 2018: Nature Immunology
https://www.readbyqxmd.com/read/29760216/-plasmodium-falciparum-msp3-exists-in-a-complex-on-the-merozoite-surface-and-generates-antibody-response-during-natural-infection
#10
Arunaditya Deshmukh, Bishwanath Kumar Chourasia, Sonali Mehrotra, Ikhlaq Hussain Kana, Gourab Paul, Ashutosh Panda, Inderjeet Kaur, Susheel Kumar Singh, Sumit Rathore, Aparup Das, Priya Gupta, Kalamuddin Md, S K Ghakar, Asif Mohmmed, Michael Theisen, Pawan Malhotra
Plasmodium falciparum merozoite surface protein 3 (MSP3) is an abundantly expressed secreted merozoite surface protein and a leading malaria vaccine candidate antigen. However, it is unclear how MSP3 is retained on the surface of merozoites without a GPI anchor or a transmembrane domain. In the present study, we identified an MSP3 associated network on the Plasmodium merozoite surface by Immunoprecipitation of Plasmodium merozoite lysate using anti-MSP3N antibodies followed by mass spectrometry analysis. The results suggested the association of MSP3 with other merozoite surface proteins; MSP1, MSP6, MSP7, RAP2 and SERA5...
May 14, 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29758480/analytical-and-clinical-performance-of-progesterone-receptor-antibodies-in-breast-cancer
#11
Benjamin C Calhoun, Brian Mosteller, Daniel Warren, Margie Smith, J Jordi Rowe, Christopher P Lanigan, Karen C Mrazeck, Espen Walker, Amy Hanlon Newell, Raymond Jones
OBJECTIVE: Comparison of analytical and immunohistochemical performance of progesterone receptor (PR) antibodies with correlation to recurrence of invasive breast cancer treated with endocrine therapy. METHODS: The binding-affinity kinetics of PR clones 1E2, 1A6, 16 and 636 were compared using synthetic peptides derived from identified epitopes on a Biacore T200. A cohort of 351 cases (Hormone Receptor (HR)+/HER2-) were stained for PR expression with immunohistochemistry (IHC) and scored according to ASCO/CAP criteria...
February 27, 2018: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/29757445/lessons-learned-from-merging-wet-lab-experiments-with-molecular-simulation-to-improve-mab-humanization
#12
L Schwaigerlehner, M Pechlaner, P Mayrhofer, C Oostenbrink, R Kunert
Humanized monoclonal antibodies (mAbs) are among the most promising modern therapeutics, but defined engineering strategies are still not available. Antibody humanization often leads to a loss of affinity, as it is the case for our model antibody Ab2/3H6 (PDB entry 3BQU). Identifying appropriate back-to-mouse mutations is needed to restore binding affinity, but highly challenging. In order to get more insight, we have applied molecular dynamics simulations and correlated them to antibody binding and expression in wet lab experiments...
May 11, 2018: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/29755477/glycan-shielding-and-modulation-of-hepatitis-c-virus-neutralizing-antibodies
#13
REVIEW
Muriel Lavie, Xavier Hanoulle, Jean Dubuisson
Hepatitis C virus (HCV) envelope glycoprotein heterodimer, E1E2, plays an essential role in virus entry and assembly. Furthermore, due to their exposure at the surface of the virion, these proteins are the major targets of anti-HCV neutralizing antibodies. Their ectodomain are heavily glycosylated with up to 5 sites on E1 and up to 11 sites on E2 modified by N-linked glycans. Thus, one-third of the molecular mass of E1E2 heterodimer corresponds to glycans. Despite the high sequence variability of E1 and E2, N-glycosylation sites of these proteins are generally conserved among the seven major HCV genotypes...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29755348/the-fibrin-cleavage-product-b%C3%AE-15-42-channels-endothelial-and-tubular-regeneration-in-the-post-acute-course-during-murine-renal-ischemia-reperfusion-injury
#14
Dania Fischer, Christopher Seifen, Patrick Baer, Michaela Jung, Christina Mertens, Bertram Scheller, Kai Zacharowski, Rainer Hofmann, Thorsten J Maier, Anja Urbschat
Early and adequate restoration of endothelial and tubular renal function is a substantial step during regeneration after ischemia reperfusion (IR) injury, occurring, e.g., in kidney transplantation, renal surgery, and sepsis. While tubular epithelial cell injury has long been of central importance, recent perception includes the renal vascular endothelium. In this regard, the fibrin cleavage product fibrinopeptide Bβ15-42 mitigate IR injury by stabilizing interendothelial junctions through its affinity to VE-cadherin...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29753204/next-generation-antibodies-for-post-translational-modifications
#15
REVIEW
Takamitsu Hattori, Shohei Koide
Despite increasing demands for antibodies to post-translational modifications (PTMs), fundamental difficulties in molecular recognition of PTMs hinder the generation of highly functional anti-PTM antibodies using conventional methods. Recently, advanced approaches in protein engineering and design that have been established for biologics development were applied to successfully generating highly functional anti-PTM antibodies. Furthermore, structural analyses of anti-PTM antibodies revealed unprecedented binding modes that substantially increased the antigen-binding surface...
May 9, 2018: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/29752180/-177-lu-psma-617-radionuclide-treatment-in-patients-with-metastatic-castration-resistant-prostate-cancer-lupsma-trial-a-single-centre-single-arm-phase-2-study
#16
Michael S Hofman, John Violet, Rodney J Hicks, Justin Ferdinandus, Sue Ping Thang, Tim Akhurst, Amir Iravani, Grace Kong, Aravind Ravi Kumar, Declan G Murphy, Peter Eu, Price Jackson, Mark Scalzo, Scott G Williams, Shahneen Sandhu
BACKGROUND: Progressive metastatic castration-resistant prostate cancer is a highly lethal disorder and new effective therapeutic agents that improve patient outcomes are urgently needed. Lutetium-177 [177 Lu]-PSMA-617, a radiolabelled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA) enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer. We aimed to investigate the safety, efficacy, and effect on quality of life of [177 Lu]-PSMA-617 in men with metastatic castration-resistant prostate cancer who progressed after standard treatments...
May 7, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29744038/generating-and-repairing-genetically-programmed-dna-breaks-during-immunoglobulin-class-switch-recombination
#17
REVIEW
Laura Nicolas, Montserrat Cols, Jee Eun Choi, Jayanta Chaudhuri, Bao Vuong
Adaptive immune responses require the generation of a diverse repertoire of immunoglobulins (Igs) that can recognize and neutralize a seemingly infinite number of antigens. V(D)J recombination creates the primary Ig repertoire, which subsequently is modified by somatic hypermutation (SHM) and class switch recombination (CSR). SHM promotes Ig affinity maturation whereas CSR alters the effector function of the Ig. Both SHM and CSR require activation-induced cytidine deaminase (AID) to produce dU:dG mismatches in the Ig locus that are transformed into untemplated mutations in variable coding segments during SHM or DNA double-strand breaks (DSBs) in switch regions during CSR...
2018: F1000Research
https://www.readbyqxmd.com/read/29742893/synthesis-liposomal-formulation-and-immunological-evaluation-of-a-minimalistic-carbohydrate-%C3%AE-galcer-vaccine-candidate
#18
Felix Broecker, Sebastian Götze, Jonathan Hudon, Dominea C K Rathwell, Claney L Pereira, Pierre Stallforth, Anish Chakkumkal, Peter H Seeberger
Fully synthetic glycan-based vaccines hold great potential as preventive and therapeutic vaccines against infectious diseases as well as cancer. Here, we present a two-component platform based on the facile conjugation of carbohydrate antigens to α-galactosylceramide (α-GalCer) to yield fully synthetic vaccine candidates. Formulation of a cancer-associated Tn antigen glycolipid model vaccine candidate into liposomes of different sizes and subsequent immunization of mice generated specific, high-affinity antibodies against the carbohydrate antigen with characteristics of T cell-dependent immunity...
May 9, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29742342/receptor-based-peptides-for-inhibition-of-rtx-leukotoxin-ltxa-activity
#19
Eric Krueger, Shannon Hayes, En Hyung Chang, Shailagne Yutuc, Angela C Brown
The Gram-negative bacterium Aggregatibacter actinomycetemcomitans, commonly associated with localized aggressive periodontitis (LAP), secretes an RTX (repeats-in-toxin) protein leukotoxin (LtxA) that targets human white blood cells, an interaction that is driven by its recognition of the lymphocyte function-associated antigen-1 (LFA-1) integrin. In this study, we report on the inhibition of LtxA-LFA-1 binding as an anti-virulence strategy to inhibit LtxA-mediated cytotoxicity. Specifically, we designed and synthesized peptides corresponding to the reported LtxA binding domain on LFA-1 and characterized their capability to inhibit LtxA binding to LFA-1 and subsequent cytotoxic activity in human immune cells...
May 9, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29741477/empty-conformers-of-hla-b-preferentially-bind-cd8-and-regulate-cd8-t-cell-function
#20
Jie Geng, John D Altman, Sujatha Krishnakumar, Malini Raghavan
When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode...
May 9, 2018: ELife
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