Site-Selective Chemoenzymatic Modification on the Core Fucose of an Antibody Enhances Its Fcγ Receptor Affinity and ADCC Activity

2021 ◽  
Author(s):  
Chao Li ◽  
Gene Chong ◽  
Guanghui Zong ◽  
David A. Knorr ◽  
Stylianos Bournazos ◽  
...  
Keyword(s):  
Adcc Activity ◽  
Fcγ Receptor ◽  
Receptor Affinity ◽  
The Core ◽  
Site Selective

scholarly journals Site-selective chemoenzymatic glycoengineering of Fab and Fc glycans of a therapeutic antibody

2018 ◽  
Vol 115 (47) ◽  
pp. 12023-12027 ◽  
Author(s):  
John P. Giddens ◽  
Joseph V. Lomino ◽  
David J. DiLillo ◽  
Jeffrey V. Ravetch ◽  
Lai-Xi Wang
Keyword(s):  
Monoclonal Antibody ◽  
Substrate Specificity ◽  
Lactobacillus Casei ◽  
Therapeutic Antibody ◽  
Adcc Activity ◽  
Therapeutic Monoclonal Antibody ◽  
The Core ◽  
Site Selectivity ◽  
Dependent Cell ◽  
Site Selective

The N-glycans attached to the Fab and Fc domains play distinct roles in modulating the functions of antibodies. However, posttranslational site-selective modifications of glycans in antibodies and other multiply glycosylated proteins remain a challenging task. Here, we report a chemoenzymatic method that permits independent manipulation of the Fab and Fc N-glycans, using cetuximab as a model therapeutic monoclonal antibody. Taking advantage of the substrate specificity of three endoglycosidases (Endo-S, Endo-S2, and Endo-F3) and their glycosynthase mutants, together with an unexpected substrate site-selectivity of a bacterial α1,6-fucosidase from Lactobacillus casei (AlfC), we were able to synthesize an optimal homogeneous glycoform of cetuximab in which the heterogeneous and immunogenic Fab N-glycans were replaced with a single sialylated N-glycan, and the core-fucosylated Fc N-glycans were remodeled with a nonfucosylated and fully galactosylated N-glycan. The glycoengineered cetuximab demonstrated increased affinity for the FcγIIIa receptor and significantly enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity.

scholarly journals Site-selective modification of peptide backbones

2021 ◽  
Author(s):  
Alicia Boto ◽  
Concepcion gonzalez ◽  
Dacil Hernández ◽  
Ivan Romero-Estudillo ◽  
Carlos Javier Javier Saavedra Fernández
Keyword(s):  
Peptide Conformation ◽  
Biological Properties ◽  
Fine Tuning ◽  
The Core ◽  
Physico Chemical ◽  
Site Selective

The site-selective modification of peptide backbones allows an outstanding fine-tuning of peptide conformation, folding ability, physico-chemical and biological properties. However, to achieve selectivity in the core of these biopolymers is...

scholarly journals A C-to-O atom-swapping reaction sequence enabled by Ni-catalyzed decarbonylation of lactones

2022 ◽  
Author(s):  
Quang H Luu ◽  
Junqi Li
Keyword(s):  
Complex Molecule ◽  
Single Atom ◽  
Reaction Sequence ◽  
The Core ◽  
Selective Functionalization ◽  
Site Selective ◽  
Core Framework

Advances in site-selective functionalization reactions have enabled single atom changes on the periphery of a complex molecule, but reaction manifolds that enable such changes on the core framework of the...

Site-selective ion production of the core-excitedCH3Fmolecule probed by Auger-electron–ion coincidence measurements

2005 ◽  
Vol 72 (4) ◽  
Author(s):  
X. J. Liu ◽  
G. Prümper ◽  
E. Kukk ◽  
R. Sankari ◽  
M. Hoshino ◽  
...  
Keyword(s):  
Auger Electron ◽  
The Core ◽  
Ion Production ◽  
Site Selective ◽  
Coincidence Measurements

scholarly journals Enhancing CDC and ADCC of CD19 Antibodies by Combining Fc Protein-Engineering with Fc Glyco-Engineering

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 63
Author(s):  
Sophia Roßkopf ◽  
Klara Marie Eichholz ◽  
Dorothee Winterberg ◽  
Katarina Julia Diemer ◽  
Sebastian Lutz ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Engineering ◽  
Amino Acid Sequence ◽  
Therapeutic Antibodies ◽  
Adcc Activity ◽  
Fcγ Receptor ◽  
Effector Functions ◽  
Complement Dependent Cytotoxicity ◽  
Dependent Cell ◽  
Cluster Of Differentiation

Background: Native cluster of differentiation (CD) 19 targeting antibodies are poorly effective in triggering antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are crucial effector functions of therapeutic antibodies in cancer immunotherapy. Both functions can be enhanced by engineering the antibody’s Fc region by altering the amino acid sequence (Fc protein-engineering) or the Fc-linked glycan (Fc glyco-engineering). We hypothesized that combining Fc glyco-engineering with Fc protein-engineering will rescue ADCC and CDC in CD19 antibodies. Results: Four versions of a CD19 antibody based on tafasitamab’s V-regions were generated: a native IgG1, an Fc protein-engineered version with amino acid exchanges S267E/H268F/S324T/G236A/I332E (EFTAE modification) to enhance CDC, and afucosylated, Fc glyco-engineered versions of both to promote ADCC. Irrespective of fucosylation, antibodies carrying the EFTAE modification had enhanced C1q binding and were superior in inducing CDC. In contrast, afucosylated versions exerted an enhanced affinity to Fcγ receptor IIIA and had increased ADCC activity. Of note, the double-engineered antibody harboring the EFTAE modification and lacking fucose triggered both CDC and ADCC more efficiently. Conclusions: Fc glyco-engineering and protein-engineering could be combined to enhance ADCC and CDC in CD19 antibodies and may allow the generation of antibodies with higher therapeutic efficacy by promoting two key functions simultaneously.

What face familiarity feelings say about the lateralization of specific entities within the core system

2019 ◽  
Vol 42 ◽  
Author(s):  
Guido Gainotti
Keyword(s):  
Temporal Lobe ◽  
Memory System ◽  
Core System ◽  
The Core ◽  
Memory Traces ◽  
Specific Memory ◽  
Target Article ◽  
Temporal Structures ◽  
The Right

Abstract The target article carefully describes the memory system, centered on the temporal lobe that builds specific memory traces. It does not, however, mention the laterality effects that exist within this system. This commentary briefly surveys evidence showing that clear asymmetries exist within the temporal lobe structures subserving the core system and that the right temporal structures mainly underpin face familiarity feelings.

A scanning electron microscopic study on dissolving process of cholesterol gallstones by chenodeoxycholic acid (CDCA)

1978 ◽  
Vol 36 (2) ◽  
pp. 522-523
Author(s):  
T. Kanetaka ◽  
M. Cho ◽  
S. Kawamura ◽  
T. Sado ◽  
K. Hara
Keyword(s):  
Electron Microscope ◽  
Chenodeoxycholic Acid ◽  
Outer Surface ◽  
Electron Microscopic ◽  
Cholesterol Gallstones ◽  
The Core ◽  
Scanning Electron Microscopic Study ◽  
Scanning Electron Microscopic ◽  
Acceleration Voltage ◽  
Scanning Electron

The authors have investigated the dissolution process of human cholesterol gallstones using a scanning electron microscope(SEM). This study was carried out by comparing control gallstones incubated in beagle bile with gallstones obtained from patients who were treated with chenodeoxycholic acid(CDCA).The cholesterol gallstones for this study were obtained from 14 patients. Three control patients were treated without CDCA and eleven patients were treated with CDCA 300-600 mg/day for periods ranging from four to twenty five months. It was confirmed through chemical analysis that these gallstones contained more than 80% cholesterol in both the outer surface and the core.The specimen were obtained from the outer surface and the core of the gallstones. Each specimen was attached to alminum sheet and coated with carbon to 100Å thickness. The SEM observation was made by Hitachi S-550 with 20 kV acceleration voltage and with 60-20, 000X magnification.

The Structure and Development of Microbodies in the Fat Body and other Tissues of an Insect (Calpodes Ethlius)

1970 ◽  
Vol 28 ◽  
pp. 148-149
Author(s):  
M. Locke ◽  
J. T. McMahon
Keyword(s):  
Electron Microscopy ◽  
Liquid Crystals ◽  
Fat Body ◽  
Competitive Inhibitor ◽  
Dense Core ◽  
Urate Oxidase ◽  
Blood Proteins ◽  
Free Base ◽  
The Core ◽  
The Matrix

The fat body of insects has always been compared functionally to the liver of vertebrates. Both synthesize and store glycogen and lipid and are concerned with the formation of blood proteins. The comparison becomes even more apt with the discovery of microbodies and the localization of urate oxidase and catalase in insect fat body.The microbodies are oval to spherical bodies about 1μ across with a depression and dense core on one side. The core is made of coiled tubules together with dense material close to the depressed membrane. The tubules may appear loose or densely packed but always intertwined like liquid crystals, never straight as in solid crystals (Fig. 1). When fat body is reacted with diaminobenzidine free base and H2O2 at pH 9.0 to determine the distribution of catalase, electron microscopy shows the enzyme in the matrix of the microbodies (Fig. 2). The reaction is abolished by 3-amino-1, 2, 4-triazole, a competitive inhibitor of catalase. The fat body is the only tissue which consistantly reacts positively for urate oxidase. The reaction product is sharply localized in granules of about the same size and distribution as the microbodies. The reaction is inhibited by 2, 6, 8-trichloropurine, a competitive inhibitor of urate oxidase.

Sign in / Sign up

Export Citation Format

Share Document