Biochemical comparison of four commercially available human α 1 -proteinase inhibitors for treatment of α 1 -antitrypsin deficiency

Boerema, David J.; An, Bo; Gandhi, Ronak P.; Papineau, Randy; Regnier, Ed; Wilder, Anna; Molitor, Alexander; Tang, Andrew; Kee, Scott M.

doi:10.1016/j.biologicals.2017.08.010

Cited by 17 publications

(8 citation statements)

References 29 publications

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“…2 B ) lies in-line within the theoretical range of 11–38% for ΔS-Cys-Alb that can be predicted based on the average plasma concentrations of albumin, Cys-Cys and Cys observed in the human population (19–21). This predicted range of ΔS-Cys-Alb does not consider the possibility that other P/S proteins, such as alpha-1-antitrypsin may consume Cys-Cys/Cys equivalents in thawed P/S (45)—potentially accounting for slightly lower mean values of ΔS-Cys-Alb than predicted in both plasma and serum. Notably, the overall degree of inter-individual variability observed would be expected for any endogenous marker of P/S integrity.…”

Section: Discussionmentioning

confidence: 78%

Delta-S-Cys-Albumin: A Lab Test that Quantifies Cumulative Exposure of Archived Human Blood Plasma and Serum Samples to Thawed Conditions*[S]

Jeffs¹,

Jehanathan²,

Thibert³

et al. 2019

Molecular & Cellular Proteomics

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Exposure of blood plasma/serum (P/S) to thawed conditions (> −30 °C) can produce biomolecular changes that skew measurements of biomarkers within archived patient samples, potentially rendering them unfit for molecular analysis. Because freeze-thaw histories are often poorly documented, objective methods for assessing molecular fitness before analysis are needed. We report a 10-μl, dilute-and-shoot, intact-protein mass spectrometric assay of albumin proteoforms called “ΔS-Cys-Albumin” that quantifies cumulative exposure of archived P/S samples to thawed conditions. The relative abundance of S-cysteinylated (oxidized) albumin in P/S increases inexorably but to a maximum value under 100% when samples are exposed to temperatures > −30 °C. The difference in the relative abundance of S-cysteinylated albumin (S-Cys-Alb) before and after an intentional incubation period that drives this proteoform to its maximum level is denoted as ΔS-Cys-Albumin. ΔS-Cys-Albumin in fully expired samples is zero. The range (mean ± 95% CI) observed for ΔS-Cys-Albumin in fresh cardiac patient P/S (n = 97) was, for plasma 12–29% (20.9 ± 0.75%) and for serum 10–24% (15.5 ± 0.64%). The multireaction rate law that governs S-Cys-Alb formation in P/S was determined and shown to predict the rate of formation of S-Cys-Alb in plasma and serum samples—a step that enables back-calculation of the time at which unknown P/S specimens have been exposed to room temperature. A blind challenge demonstrated that ΔS-Cys-Albumin can detect exposure of groups (n = 6 each) of P/S samples to 23 °C for 2 h, 4 °C for 16 h, or −20 °C for 24 h—and exposure of individual specimens for modestly increased times. An unplanned case study of nominally pristine serum samples collected under NIH-sponsorship demonstrated that empirical evidence is required to ensure accurate knowledge of archived P/S biospecimen storage history.

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Section: Discussionmentioning

confidence: 78%

Delta-S-Cys-Albumin: A Lab Test that Quantifies Cumulative Exposure of Archived Human Blood Plasma and Serum Samples to Thawed Conditions*[S]

Jeffs¹,

Jehanathan²,

Thibert³

et al. 2019

Molecular & Cellular Proteomics

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“…Current licensed treatment for AATD includes weekly infusions (60 mg/kg/week) of AAT; a variety of preparations are available, some of which may have advantages for patients. These second-generation products offer superior purity and, hence, higher specific activity, 73 which allows for faster infusion times, making treatment more convenient for patients. The differences between AAT preparations highlight a need for increased awareness of the available treatment options and the potential differences in individual patient tolerance.…”

Section: Discussionmentioning

confidence: 99%

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications

Chorostowska‐Wynimko¹,

Koczulla²,

Ferrarotti

et al. 2018

COPD

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Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used to maintain levels above the protective threshold. Based on its biochemical efficacy, AAT replacement therapy was approved by the US Food and Drug administration in 1987. However, there remained considerable interest in selecting appropriate outcome measures that could confirm clinical efficacy in a randomized controlled trial setting. Using computed tomography as the primary measure of decline in lung density, the capacity for intravenously administered AAT replacement therapy to slow and modify the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications for clinical considerations with respect to diagnosis, treatment and management of emphysema due to alpha 1 antitrypsin deficiency.

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“…To begin with, there are certain differences between these two presentations [49]. First, it has been reported in biochemical comparisons between both that Zemaira/Respreeza shows a better profile in terms of total protein content, AAT potency, specific AAT activity, and purity [50,51]. Secondly, the concentration of AAT is different in both preparations with Zemaira/Respreeza having a higher concentration (Table 2).…”

Section: Differences Between Preparationsmentioning

confidence: 99%

Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

Lόpez-Campos

Hernández

Eraso

2020

JCM

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Ever since the first studies, restoring proteinase imbalance in the lung has traditionally been considered as the main goal of alpha1 antitrypsin (AAT) replacement therapy. This strategy was therefore based on ensuring biochemical efficacy, identifying a protection threshold, and evaluating different dosage regimens. Subsequently, the publication of the results of the main clinical trials showing a decrease in the progression of pulmonary emphysema has led to a debate over a possible change in the main objective of treatment, from biochemical efficacy to clinical efficacy in terms of lung densitometry deterioration prevention. This new paradigm has produced a series controversies and unanswered questions which face clinicians managing AAT deficiency. In this review, the concepts that led to the approval of AAT replacement therapy are reviewed and discussed under a new prism of achieving clinical efficacy, with the reduction of lung deterioration as the main objective. Here, we propose the use of current knowledge and clinical experience to face existing challenges in different clinical scenarios, in order to help clinicians in decision-making, increase interest in the disease, and stimulate research in this field.

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Biochemical comparison of four commercially available human α 1 -proteinase inhibitors for treatment of α 1 -antitrypsin deficiency

Cited by 17 publications

References 29 publications

Delta-S-Cys-Albumin: A Lab Test that Quantifies Cumulative Exposure of Archived Human Blood Plasma and Serum Samples to Thawed Conditions*[S]

Delta-S-Cys-Albumin: A Lab Test that Quantifies Cumulative Exposure of Archived Human Blood Plasma and Serum Samples to Thawed Conditions*[S]

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications

Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

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