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Anti-ApoA-I IgG antibodies are not associated with carotid artery disease progression and first-time cardiovascular events in middle-aged individuals.
Lagerstedt, JO, Dalla-Riva, J, Marinkovic, G, Del Giudice, R, Engelbertsen, D, Burlin, J, Petrlova, J, Lindahl, M, Bernfur, K, Melander, O, et al
Journal of internal medicine. 2019;(1):49-58
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Abstract
OBJECTIVE IgG antibodies against apolipoprotein A-I (ApoA-I) have been found to be elevated in subjects from the general population with clinically manifest cardiovascular disease and in myocardial infarction patients with an adverse prognosis. Here, we investigated whether these antibodies are prospectively associated with carotid artery disease progression and with the risk for first-time cardiovascular events in individuals with no previous history of cardiovascular disease. APPROACH AND RESULTS We selected 383 subjects from the cardiovascular cohort of Malmö Diet and Cancer study who suffered a coronary event during a median follow-up period of 15.4 (10.3-16.4) years and 395 age- and sex-matched controls. None of the study participants had a previous history of coronary artery disease or stroke. Anti-ApoA-I IgG were measured by ELISA in serum samples collected at baseline. Intima-media thickness (IMT) was measured in the common carotid artery and in the carotid bifurcation at baseline and after 15.9 (±1.5) years. We found no associations between anti-ApoA-I IgG and carotid artery IMT at baseline or with IMT progression during follow-up. In Cox proportional hazards analyses adjusted for traditional cardiovascular risk factors, the hazard ratio (HR 95%CI) for the primary outcome, incident coronary events, was 0.97 (0.75-1.25), P = 0.782, in subjects with anti-ApoA-I IgG within the highest tertile compared with the lowest tertile. Similarly, we did not find any associations with the secondary outcome, incident first-time stroke. CONCLUSIONS Serum autoantibodies against ApoA-I do not correlate with disease progression and adverse events in cardiovascular disease-free individuals from the general population.
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Ara h 7 isoforms share many linear epitopes: Are 3D epitopes crucial to elucidate divergent abilities?
Ehlers, AM, Klinge, M, Suer, W, Weimann, Y, Knulst, AC, Besa, F, Le, TM, Otten, HG
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(11):1512-1519
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Abstract
BACKGROUND The peanut allergens Ara h 2, h 6, and h 7 are potent allergens and can trigger severe reactions. Ara h 7 consists of three isoforms differing in their ability to induce basophil degranulation, whereas the ability of Ara h 7.0201 is comparable to Ara h 2 and 6 as shown in previous literature. OBJECTIVE To identify linear epitopes of Ara h 7.0101, Ara h 7.0201 and Ara h 7.0301 recognized by IgE and IgG4 from patients sensitized to Ara h 7 and to investigate their potential to elucidate divergent abilities of the Ara h 7 isoforms in inducing basophil activation. METHODS Linear epitopes recognized by IgE and IgG4 were mapped by peptide microarray analysis containing 15-mer peptides of Ara h 2.0201, 6, 7.0101, 7.0201 and 7.0301 and 39 peanut allergic patients sensitized to Ara h 7 (discovery). For validation, 20-mer peptides containing the minimal epitope and surrounding amino acids were incubated with 25 sensitized patients and 10 controls (validation). RESULTS Three out of 14 linear epitopes were unique for each isoform (Ara h 7.0101: aa 97-109; Ara h 7.0201: aa 122-133; Ara h 7.0301: aa 65-74) but scarcely recognized by IgE. The main linear IgE epitope (aa 51-57) located in the long flexible loop of all Ara h 7 isoforms was bound by antibodies from 31% of the patients (discovery and validation cohort). Regarding IgG4, 55% of the patients recognized an epitope present on all isoforms (aa 55-65), whereas epitope aa 129-137, only present on Ara h 7.0101/0.0301, was recognized by 38% of the patients. Recognition was highly individual, although 20% of the patients recognized any linear epitope neither by IgE nor by IgG4 despite a low mean z-score of ≥ 1.7. Remarkably, only 50% of the patients recognized one or more epitopes by IgE. CONCLUSION & CLINICAL RELEVANCE Ara h 7 isoforms share many linear epitopes being easily accessible for antibody binding. Unique epitopes, essential to elucidate divergent potencies, were scarcely recognized, suggesting a crucial involvement of conformational epitopes.
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Association between Sodium Intake and Urinary Fractional Albumin and Immunoglobulin G Excretion in Chronic Nondialytic Renal Disease: A Prospective Longitudinal Study.
Martinez, MG, Dos Santos Silva, V, do Valle, AP, de Oliveira, RC, Banin, VB, Hokama, NK, Martin, LC
Nephron. 2019;(1):62-67
Abstract
BACKGROUND/AIMS: Previous studies reported that fractional clearance of urinary proteins is better than total proteinuria in predicting chronic kidney disease (CKD) progression. However, the role of sodium in the fractional excretion of proteins has not been established. We aimed to evaluate the association between sodium intake and fractional albumin and immunoglobulin G (IgG) excretion in nondialytic CKD. METHODS We did a longitudinal, observational, and prospective study that included CKD patients aged 18-80. Included patients performed basal routine laboratory evaluations, urinary sodium excretion, and fractional albumin and IgG excretion that were repeated after 6-month of follow-up. RESULTS We evaluated 84 patients, mean age 55 ± 15.6 years, 40 women, and 74 whites. The change of estimated sodium intake had an association with the change of fractional albumin (R = 0.54; p < 0.001) and IgG (R = 0.56; p < 0.001) excretion in univariate analysis (increases in sodium intake were paralleled by increases in albumin and IgG excretion fractions). This association was maintained in a multiple generalized linear model even after adjusting for age and for changes in blood pressure, urinary potassium, protein intake, and blood glucose. CONCLUSION In CKD patients, changes in estimated sodium intake were associated with changes in the fractional albumin and IgG excretion regardless of confounding factors. Findings of this study support the idea that reducing salt intake, and consequently, albumin and IgG fractional excretions could help to slow CKD progression. This hypothesis must be tested in long-term interventional studies.
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The Core Fucose on an IgG Antibody is an Endogenous Ligand of Dectin-1.
Manabe, Y, Marchetti, R, Takakura, Y, Nagasaki, M, Nihei, W, Takebe, T, Tanaka, K, Kabayama, K, Chiodo, F, Hanashima, S, et al
Angewandte Chemie (International ed. in English). 2019;(51):18697-18702
Abstract
The core fucose, a major modification of N-glycans, is implicated in immune regulation, such as the attenuation of the antibody-dependent cell-mediated cytotoxicity of antibody drugs and the inhibition of anti-tumor responses via the promotion of PD-1 expression on T cells. Although the core fucose regulates many biological processes, no core fucose recognition molecule has been identified in mammals. Herein, we report that Dectin-1, a known anti-β-glucan lectin, recognizes the core fucose on IgG antibodies. A combination of biophysical experiments further suggested that Dectin-1 recognizes aromatic amino acids adjacent to the N-terminal asparagine at the glycosylation site as well as the core fucose. Thus, Dectin-1 appears to be the first lectin-like molecule involved in the heterovalent and specific recognition of characteristic N-glycans on antibodies.
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Studying Excipient Modulated Physical Stability and Viscosity of Monoclonal Antibody Formulations Using Small-Angle Scattering.
Xu, AY, Castellanos, MM, Mattison, K, Krueger, S, Curtis, JE
Molecular pharmaceutics. 2019;(10):4319-4338
Abstract
Excipients are substances that are added to therapeutic products to improve stability, bioavailability, and manufacturability. Undesirable protein-protein interactions (PPI) can lead to self-association and/or high solution viscosity in concentrated protein formulations that are typically greater than 50 mg/mL. Therefore, understanding the effects of excipients on nonspecific PPI is important for more efficient formulation development. In this study, we used National Institute of Standards and Technology monoclonal antibody (NISTmAb) reference material as a model antibody protein to examine the physical stability and viscosity of concentrated formulations using a series of excipients, by varying pH, salt composition, and the presence of cosolutes including amino acids, sugars, and nonionic surfactants. Small angle X-ray scattering (SAXS) together with differential scanning calorimetry (DSC), dynamic light scattering (DLS), and viscosity measurements were used to obtain various experimental parameters to characterize excipient modulated PPI and bulk solution viscosities. In particular, a good correlation was found between SAXS and DLS/SLS results, suggesting that the use of DLS/SLS is valid for predicting the colloidal stability of NISTmAb in concentrated solutions. Moreover, further analysis of effective structure factor S(q)eff measured from SAXS enabled the dissection of net PPI into hydrodynamic forces due to excluded volume as well as any additional attractive or repulsive interactions with the presence of excipients. It was found that although no denaturation or aggregation of NISTmAb was observed and that the net PPI were repulsive, the use of ionic excipients such as pH and salts leads to increased short-range attraction, whereas the nonionic excipients including sugars, amino acids, and polysorbate surfactants lead to increased repulsive PPI with increasing protein concentration. Results obtained from viscosity measurements showed that the use of excipients can lead to increased solution viscosities at high protein concentrations. The use of S(q)eff, interaction parameter kD, and second virial coefficient B22 as predictors for solution viscosity was also evaluated by comparing the predicted results with the measured viscosities. Although B22 and S(q)eff appeared to be better predictors than kD, disagreement between the predicted and measured results suggests other factors apart from PPI contribute to the bulk rheological properties of concentrated protein solutions.
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Multistage continuous countercurrent diafiltration for formulation of monoclonal antibodies.
Jabra, MG, Yehl, CJ, Zydney, AL
Biotechnology progress. 2019;(4):e2810
Abstract
There is growing interest in the development of fully integrated and continuous biomanufacturing processes for the production of monoclonal antibody products. A recent study has demonstrated the feasibility of using a two-stage countercurrent diafiltration (DF) process for continuous product formulation, but this system did not provide sufficient levels of buffer exchange for most applications. The objective of this study was to design and test a three-stage countercurrent DF system that could achieve at least 99.9% buffer exchange over 24 hr of continuous operation. Experimental data were obtained using concentrated solutions of human immunoglobulin G as a model protein, with the extent of vitamin B12 removal used to track the extent of DF. Pall Cadence™ inline concentrators with Delta 30 kD regenerated cellulose membranes were used in the three stages to achieve high conversion in a single pass. The three-stage system showed stable operation with >99.9% vitamin B12 removal and a minimal increase in pressure over the full 24 hr. Modules were effectively cleaned using sodium hydroxide, with nearly complete recovery of water permeability. A simple economic analysis was presented that accounts for the trade-offs between quantity of buffer used and membrane costs for this type of countercurrent staged DF process. The results provide important insights to the design and operation of a continuous process for antibody formulation.
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The IgG2 Isotype of Anti-Transcription Intermediary Factor 1γ Autoantibodies Is a Biomarker of Cancer and Mortality in Adult Dermatomyositis.
Aussy, A, Fréret, M, Gallay, L, Bessis, D, Vincent, T, Jullien, D, Drouot, L, Jouen, F, Joly, P, Marie, I, et al
Arthritis & rheumatology (Hoboken, N.J.). 2019;(8):1360-1370
Abstract
OBJECTIVE Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM. METHODS This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model. RESULTS Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality. CONCLUSION Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.
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Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia.
Kishnani, PS, Rockman-Greenberg, C, Rauch, F, Bhatti, MT, Moseley, S, Denker, AE, Watsky, E, Whyte, MP
Bone. 2019;:149-162
Abstract
Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa 0.3 mg/kg/d subcutaneously (SC; n = 7), asfotase alfa 0.5 mg/kg/d SC (n = 6), or no treatment (control; n = 6) for 6 months. In the extension phase, patients received asfotase alfa (0.5 mg/kg/d for 6 mo-1 y, then 1 mg/kg/d 6 d/wk). During the primary treatment period, changes from Baseline to Month 6 in plasma PLP and PPi concentrations (coprimary efficacy measure) were greater in the combined asfotase alfa group compared with the control group, reaching statistical significance for PLP (P = 0.0285) but not for PPi (P = 0.0715). However, for the total cohort, the within subject changes in both PLP and PPi after 6 months and over 5 years of treatment with asfotase alfa were significant (P < 0.05). Secondary efficacy measures included transiliac crest histomorphometry, dual-energy X-ray absorptiometry (DXA), and the 6-Minute Walk Test (6MWT). A significant decrease from Baseline in mineralization lag time was observed in the combined asfotase alfa group at Year 1. There were no significant differences between treated and control patients in DXA mean bone mineral density results at 6 months; Z-scores and T-scores were within the expected range for age at Baseline and remained so over 5 years of treatment. On the 6MWT, median (min, max) distance walked increased from 355 (10, 620; n = 19) meters before treatment to 450 (280, 707; n = 13) meters at 5 years (P < 0.05). Results for the exploratory outcome measures suggested improvements in gross motor function, muscle strength, and patient-reported functional disability over 5 years of treatment. There were no deaths during this study. Asfotase alfa was generally well tolerated; the most common adverse events were mild to moderate injection site reactions. This study suggests that in adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa is associated with normalization of circulating TNSALP substrate levels and improved functional abilities.
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Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study.
Hofmann, CE, Harmatz, P, Vockley, J, Högler, W, Nakayama, H, Bishop, N, Martos-Moreno, GÁ, Moseley, S, Fujita, KP, Liese, J, et al
The Journal of clinical endocrinology and metabolism. 2019;(7):2735-2747
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Abstract
CONTEXT Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited. OBJECTIVE To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years. DESIGN Phase 2 open-label study (July 2010 to September 2016). SETTING Twenty-two sites; 12 countries. PARTICIPANTS Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months. INTERVENTION Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously. MAIN OUTCOME MEASURES Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2). RESULTS During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment. CONCLUSIONS Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
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Relationship between serum levels of immunoglobulins and metabolic syndrome in an adult population: A population study from the TCLSIH cohort study.
Wang, X, Fu, J, Gu, Y, Chi, VTQ, Zhang, Q, Liu, L, Meng, G, Yao, Z, Wu, H, Bao, X, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2019;(9):916-922
Abstract
BACKGROUND AND AIMS Metabolic syndrome (MetS) is a combination of metabolic disorders that increase the risk of developing cardiovascular disease, and inflammation is considered as a pathological basis for MetS. Immunoglobulins (Igs) are the major secretory products of the adaptive immune system. However, no large-scale population study has focused on a possible relationship between Igs and MetS. We designed a cross-sectional study to investigate the relationship between Igs and prevalence of MetS in a large-scale adult population. METHODS AND RESULTS A total of 10,289 participants were recruited among residents in Tianjin, China. Metabolic syndrome was defined in accordance with the criteria of the American Heart Association scientific statements of 2009. Serum levels of Igs were determined by immunonephelometry. Multiple logistic regression models were used to assess the relationship between the quintiles of serum levels of Igs and the prevalence of MetS. The overall prevalence of MetS was 36.1%. The mean (standard deviation) values of Igs (IgG, IgE, IgM, and IgA) were 1205.7 (249.3) mg/dL, 93.1 (238.9) IU/mL, 105.7 (57.3) mg/dL, and 236.2 (97.6) mg/dL, respectively. The adjusted odds ratios (95% confidence interval) of MetS for the highest quintile of Igs (IgG, IgE, IgM, and IgA), when compared to the lowest quintile, were 0.81 (0.70, 0.95), 0.97 (0.83, 1.12), 1.13 (0.97, 1.33), and 1.52 (1.30, 1.77), respectively. CONCLUSIONS This study demonstrated that decreased IgG and increased IgA are independently related to a higher prevalence of MetS. The results indicate that the Igs might be useful predictive factors for MetS in the general adult population.