scholarly journals IgG light chain-independent secretion of heavy chain dimers: consequence for therapeutic antibody production and design

2017 ◽  
Vol 474 (18) ◽  
pp. 3179-3188 ◽  
Author(s):  
Chloe L. Stoyle ◽  
Paul E. Stephens ◽  
David P. Humphreys ◽  
Sam Heywood ◽  
Katharine Cain ◽  
...  
Keyword(s):  
Quality Control ◽  
Heavy Chain ◽  
Light Chain ◽  
Recombinant Antibody ◽  
Control Process ◽  
Efficient Production ◽  
Biological Targets ◽  
Heavy Chains ◽  
Quality Control Process

Rodent monoclonal antibodies with specificity towards important biological targets are developed for therapeutic use by a process of humanisation. This process involves the creation of molecules, which retain the specificity of the rodent antibody but contain predominantly human coding sequence. Here, we show that some humanised heavy chains (HCs) can fold, form dimers and be secreted even in the absence of a light chain (LC). Quality control of recombinant antibody assembly in vivo is thought to rely upon folding of the HC CH1 domain. This domain acts as a switch for secretion, only folding upon interaction with the LC CL domain. We show that the secreted heavy-chain dimers contain folded CH1 domains and contribute to the heterogeneity of antibody species secreted during the expression of therapeutic antibodies. This subversion of the normal quality control process is dependent on the HC variable domain, is prevalent with engineered antibodies and can occur when only the Fab fragments are expressed. This discovery will have an impact on the efficient production of both humanised antibodies and the design of novel antibody formats.

scholarly journals The Pathway of Us11-Dependent Degradation of Mhc Class I Heavy Chains Involves a Ubiquitin-Conjugated Intermediate

1999 ◽  
Vol 147 (1) ◽  
pp. 45-58 ◽  
Author(s):  
Caroline E. Shamu ◽  
Craig M. Story ◽  
Tom A. Rapoport ◽  
Hidde L. Ploegh
Keyword(s):  
Mhc Class I ◽  
Heavy Chain ◽  
Control Process ◽  
Degradation Pathway ◽  
Cell System ◽  
Class I ◽  
Permeabilized Cell ◽  
Intact Cells ◽  
Heavy Chains ◽  
Quality Control Process

The human cytomegalovirus protein, US11, initiates the destruction of MHC class I heavy chains by targeting them for dislocation from the ER to the cytosol and subsequent degradation by the proteasome. We report the development of a permeabilized cell system that recapitulates US11-dependent degradation of class I heavy chains. We have used this system, in combination with experiments in intact cells, to identify and order intermediates in the US11-dependent degradation pathway. We find that heavy chains are ubiquitinated before they are degraded. Ubiquitination of the cytosolic tail of heavy chain is not required for its dislocation and degradation, suggesting that ubiquitination occurs after at least part of the heavy chain has been dislocated from the ER. Thus, ubiquitination of the heavy chain does not appear to be the signal to start dislocation. Ubiquitinated heavy chains are associated with membrane fractions, suggesting that ubiquitination occurs while the heavy chain is still bound to the ER membrane. Our results support a model in which US11 co-opts the quality control process by which the cell destroys misfolded ER proteins in order to specifically degrade MHC class I heavy chains.

scholarly journals BiP and Immunoglobulin Light Chain Cooperate to Control the Folding of Heavy Chain and Ensure the Fidelity of Immunoglobulin Assembly

1999 ◽  
Vol 10 (7) ◽  
pp. 2209-2219 ◽  
Author(s):  
Young-Kwang Lee ◽  
Joseph W. Brewer ◽  
Rachel Hellman ◽  
Linda M. Hendershot
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
Protein Complexes ◽  
Critical Role ◽  
Light Chains ◽  
Heavy Chains ◽  
Chain Complexes ◽  
Chain Synthesis

The immunoglobulin (Ig) molecule is composed of two identical heavy chains and two identical light chains (H2L2). Transport of this heteromeric complex is dependent on the correct assembly of the component parts, which is controlled, in part, by the association of incompletely assembled Ig heavy chains with the endoplasmic reticulum (ER) chaperone, BiP. Although other heavy chain-constant domains interact transiently with BiP, in the absence of light chain synthesis, BiP binds stably to the first constant domain (CH1) of the heavy chain, causing it to be retained in the ER. Using a simplified two-domain Ig heavy chain (VH-CH1), we have determined why BiP remains bound to free heavy chains and how light chains facilitate their transport. We found that in the absence of light chain expression, the CH1 domain neither folds nor forms its intradomain disulfide bond and therefore remains a substrate for BiP. In vivo, light chains are required to facilitate both the folding of the CH1 domain and the release of BiP. In contrast, the addition of ATP to isolated BiP–heavy chain complexes in vitro causes the release of BiP and allows the CH1 domain to fold in the absence of light chains. Therefore, light chains are not intrinsically essential for CH1 domain folding, but play a critical role in removing BiP from the CH1 domain, thereby allowing it to fold and Ig assembly to proceed. These data suggest that the assembly of multimeric protein complexes in the ER is not strictly dependent on the proper folding of individual subunits; rather, assembly can drive the complete folding of protein subunits.

scholarly journals Immunoglobulin heavy chain and binding protein complexes are dissociated in vivo by light chain addition.

1990 ◽  
Vol 111 (3) ◽  
pp. 829-837 ◽  
Author(s):  
L M Hendershot
Keyword(s):  
Heavy Chain ◽  
Light Chain ◽  
Secretory Pathway ◽  
Protein Transport ◽  
Protein Complexes ◽  
Binding Protein ◽  
Immunoglobulin Heavy Chain ◽  
Light Chains ◽  
Heavy Chains

Immunoglobulin heavy chain binding protein (BiP, GRP78) associates stably with the free, nonsecreted Ig heavy chains synthesized by Abelson virus transformed pre-B cell lines. In cells synthesizing both Ig heavy and light chains, the Ig subunits assemble rapidly and are secreted. Only incompletely assembled Ig molecules can be found bound to BiP in these cells. In addition to Ig heavy chains, a number of mutant and incompletely glycosylated transport-defective proteins are stably complexed with BiP. When normal proteins are examined for combination with BiP, only a small fraction of the intracellular pool of nascent, unfolded, or unassembled proteins can be found associated. It has been difficult to determine whether these BiP-associated molecules represent assembly intermediates which will be displaced from BiP and transported from the cell, or whether these are aberrant proteins that are ultimately degraded. In order for BiP to monitor and aid in normal protein transport, its association with these proteins must be reversible and the released proteins should be transport competent. In the studies described here, transient heterokaryons were formed between a myeloma line producing BiP-associated heavy chains and a myeloma line synthesizing the complementary light chain. Introduction of light chain synthesis resulted in assembly of prelabeled heavy chains with light chains, displacement of BiP from heavy chains, and secretion of Ig into the culture supernatant. These data demonstrate that BiP association can be reversible, with concordant release of transportable proteins. Thus, BiP can be considered a component of the exocytic secretory pathway, regulating the transport of both normal and abnormal proteins.

scholarly journals Design principles for the glycoprotein quality control pathway

2021 ◽  
Vol 17 (2) ◽  
pp. e1008654
Author(s):  
Aidan I. Brown ◽  
Elena F. Koslover
Keyword(s):  
Quality Control ◽  
Protein Production ◽  
Control Process ◽  
Design Principles ◽  
Folding Rate ◽  
Quality Control Process ◽  
Energy Consuming ◽  
Alternative Designs ◽  
Glycoprotein Quality Control

Newly-translated glycoproteins in the endoplasmic reticulum (ER) often undergo cycles of chaperone binding and release in order to assist in folding. Quality control is required to distinguish between proteins that have completed native folding, those that have yet to fold, and those that have misfolded. Using quantitative modeling, we explore how the design of the quality-control pathway modulates its efficiency. Our results show that an energy-consuming cyclic quality-control process, similar to the observed physiological system, outperforms alternative designs. The kinetic parameters that optimize the performance of this system drastically change with protein production levels, while remaining relatively insensitive to the protein folding rate. Adjusting only the degradation rate, while fixing other parameters, allows the pathway to adapt across a range of protein production levels, aligning with in vivo measurements that implicate the release of degradation-associated enzymes as a rapid-response system for perturbations in protein homeostasis. The quantitative models developed here elucidate design principles for effective glycoprotein quality control in the ER, improving our mechanistic understanding of a system crucial to maintaining cellular health.

Analysis of the information management system in the manufacturing process of cigarette enterprises using fuzzy AHP

2021 ◽  
pp. 1-11
Author(s):  
Song Gang ◽  
Wang Xiaoming ◽  
Wu Junfeng ◽  
Li Shufang ◽  
Liu Zhuowen ◽  
...  
Keyword(s):  
Quality Control ◽  
Production Process ◽  
Information Management ◽  
Manufacturing Process ◽  
Management System ◽  
Fuzzy Ahp ◽  
Control Process ◽  
Information Management System ◽  
Manufacturing Execution System ◽  
Quality Control Process

In view of the production quality management of filter rods in the manufacturing and execution process of cigarette enterprises, this paper analyzes the necessity of implementing the manufacturing execution system (MES) in the production process of filter rods. In this paper, the filter rod quality system of cigarette enterprise based on MES is fully studied, and the constructive information management system demand analysis, cigarette quality control process, system function module design, implementation and test effect are given. This paper utilizes the Fuzzy analytic hierarchy process to find the optimal system for processing the manufacturing of cigarette. The implementation of MSE based filter rod quality information management system for a cigarette enterprise ensures the quality control in the cigarette production process. Through visualization, real-time and dynamic way, the information management of cigarette production is completed, which greatly improves the quality of cigarette enterprise manufacturing process.

Mitocytosis, a migrasome-mediated mitochondrial quality-control process

Cell ◽  
2021 ◽  
Vol 184 (11) ◽  
pp. 2896-2910.e13
Author(s):  
Haifeng Jiao ◽  
Dong Jiang ◽  
Xiaoyu Hu ◽  
Wanqing Du ◽  
Liangliang Ji ◽  
...  
Keyword(s):  
Quality Control ◽  
Control Process ◽  
Mitochondrial Quality Control ◽  
Quality Control Process

scholarly journals A Two-Stage Quality Control Method for 2-m Temperature Observations Using Biweight Means and a Progressive EOF Analysis

2013 ◽  
Vol 141 (2) ◽  
pp. 798-808 ◽  
Author(s):  
Zhifang Xu ◽  
Yi Wang ◽  
Guangzhou Fan
Keyword(s):  
Quality Control ◽  
Control Method ◽  
Control Process ◽  
Lapse Rate ◽  
Systematic Bias ◽  
Eof Analysis ◽  
Two Stage ◽  
Quality Control Method ◽  
Quality Control Process ◽  
The Difference

Abstract The relatively smooth terrain embedded in the numerical model creates an elevation difference against the actual terrain, which in turn makes the quality control of 2-m temperature difficult when forecast or analysis fields are utilized in the process. In this paper, a two-stage quality control method is proposed to address the quality control of 2-m temperature, using biweight means and a progressive EOF analysis. The study is made to improve the quality control of the observed 2-m temperature collected by China and its neighboring areas, based on the 6-h T639 analysis from December 2009 to February 2010. Results show that the proposed two-stage quality control method can secure the needed quality control better, compared with a regular EOF quality control process. The new method is, in particular, able to remove the data that are dotted with consecutive errors but showing small fluctuations. Meanwhile, compared with the lapse rate of temperature method, the biweight mean method is able to remove the systematic bias generated by the model. It turns out that such methods make the distributions of observation increments (the difference between observation and background) more Gaussian-like, which ensures the data quality after the quality control.

scholarly journals Blockchain in manufacturing quality control: A computer simulation study

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247925
Author(s):  
Pooi-Mun Wong ◽  
Shreya R. K. Sinha ◽  
Chee-Kong Chui
Keyword(s):  
Quality Control ◽  
Data Security ◽  
Control Process ◽  
Production Quality ◽  
Consensus Algorithm ◽  
Defect Tolerance ◽  
Production Quality Control ◽  
Peer Supervision ◽  
Quality Control Process ◽  
Quality Controller

Blockchain has been applied to quality control in manufacturing, but the problems of false defect detections and lack of data transparency remain. This paper proposes a framework, Blockchain Quality Controller (BCQC), to overcome these limitations while fortifying data security. BCQC utilizes blockchain and Internet-of-Things to form a peer-to-peer supervision network. This paper also proposes a consensus algorithm, Quality Defect Tolerance (QDT), to adopt blockchain for during-production quality control. Simulation results show that BCQC enhances data security and improves defect detections. Although the time taken for the quality control process increases with the number of nodes in blockchain, the application of QDT allows multiple inspections on a workpiece to be consolidated at a faster pace, effectively speeding up the entire quality control process. The BCQC and QDT can improve the quality of parts produced for mass personalization manufacturing.

scholarly journals PENERAPAN STATISTICAL QUALITY CONTROL (SQC) PADA PENGENDALIAN MUTU MINYAK TELON (STUDI KASUS DI PT.X)

AGROINTEK ◽  
2019 ◽  
Vol 13 (1) ◽  
pp. 72
Author(s):  
Andan Linggar Rucitra ◽  
S Fadiah
Keyword(s):  
Quality Control ◽  
Raw Materials ◽  
Control Process ◽  
Statistical Quality Control ◽  
Statistical Quality ◽  
Quality Control Process ◽  
Fishbone Diagram ◽  
Potential Factor ◽  
Measurement Of Success

<p><em>Telon oil is</em><em> one of </em><em> </em><em>the </em><em>traditional medicine in the form of </em><em> </em><em>liquid preparations that serves to provide a sense of warmth to the wearer. PT</em><em>.X</em><em> is one of the companies that produce</em><em> </em><em>telon</em><em> oil</em><em>.</em><em> To maintain</em><em> the quality of telon oil from PT.X</em><em> product</em><em>, required overall quality control that is starting from the quality control of raw materials, quality control process to the quality control of the final product. The purpose of this research is to know the application of Statistical Quality Control (SQC) in controlling the quality of telon oil in PT X. </em><em>F</em><em>inal product</em><em> quality</em><em> become one of the measurement of success of a process, so it needs a good quality control. SQC method used in this research is Pareto Diagram and Cause and Effect Diagram. Pareto diagram is a bar graph </em><em>that </em><em>show the problem based on the order of the number of occurrences of the most number of problems until the least happened. A causal diagram is often called a fishbone diagram, a tool for identifying potential causes of an effect or problem. The result of applying the method indicates that 80% defect is caused by unsuitable volume and on the incompatibility of Expired Date (ED) code. The damage is caused by several factors namely the method, labor, and machine while the most potential factor is the volume conformity to reduce the number of defect products.</em></p>

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