scholarly journals Monoclonal Antibodies Targeting Ion Channels and Their Therapeutic Potential

2019 ◽  
Vol 10 ◽  
Author(s):  
Aurélien Haustrate ◽  
Aline Hantute-Ghesquier ◽  
Natalia Prevarskaya ◽  
V’yacheslav Lehen’kyi
Keyword(s):  
Monoclonal Antibodies ◽  
Ion Channels ◽  
Therapeutic Potential

scholarly journals Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels

2021 ◽  
Vol 14 ◽  
Author(s):  
Deepanjali Dwivedi ◽  
Upinder S. Bhalla
Keyword(s):  
Ion Channels ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Brain Regions ◽  
Channel Activity ◽  
Current Review ◽  
Cellular Excitability ◽  
M Channels ◽  
Neuronal Functions

SK, HCN, and M channels are medium afterhyperpolarization (mAHP)-mediating ion channels. The three channels co-express in various brain regions, and their collective action strongly influences cellular excitability. However, significant diversity exists in the expression of channel isoforms in distinct brain regions and various subcellular compartments, which contributes to an equally diverse set of specific neuronal functions. The current review emphasizes the collective behavior of the three classes of mAHP channels and discusses how these channels function together although they play specialized roles. We discuss the biophysical properties of these channels, signaling pathways that influence the activity of the three mAHP channels, various chemical modulators that alter channel activity and their therapeutic potential in treating various neurological anomalies. Additionally, we discuss the role of mAHP channels in the pathophysiology of various neurological diseases and how their modulation can alleviate some of the symptoms.

scholarly journals Atomistic Insights of Calmodulin Gating of Complete Ion Channels

2020 ◽  
Vol 21 (4) ◽  
pp. 1285 ◽  
Author(s):  
Eider Núñez ◽  
Arantza Muguruza-Montero ◽  
Alvaro Villarroel
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Therapeutic Potential ◽  
Structural Information ◽  
Lipid Binding ◽  
Channel Structure ◽  
Extracellular Medium ◽  
Alpha Helices ◽  
Functional Studies ◽  
Direct Binding

Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K+, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca2+. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential.

scholarly journals The impact of thioredoxin reduction of allosteric disulfide bonds on the therapeutic potential of monoclonal antibodies

2019 ◽  
Vol 294 (51) ◽  
pp. 19616-19634 ◽  
Author(s):  
Shalom A. Gurjar ◽  
Jun X. Wheeler ◽  
Meenu Wadhwa ◽  
Robin Thorpe ◽  
Ian Kimber ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Disulfide Bonds ◽  
Therapeutic Potential ◽  
The Impact

Human FcγRIII (CD16) Polymorphism Screening Is Enhanced with Pyrosequencing Analysis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4911-4911
Author(s):  
Ksenia Matlawska-Wasowska ◽  
James Gale ◽  
Parisa Khalili ◽  
Bridget S Wilson ◽  
Mohammad Vasef ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cancer Cells ◽  
Targeted Therapies ◽  
Nested Pcr ◽  
Immune Cell ◽  
Conflicts Of Interest ◽  
Therapeutic Potential ◽  
Allelic Polymorphism ◽  
Allele Specific ◽  
Specific Restriction

Abstract Abstract 4911 Surface specific antigens expressed on the cell membrane of hematopoietic cells are attractive target for antibody mediated cancer cells therapy. Monoclonal antibodies involve various mechanisms to eliminate cancer cells, including antibody dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) mediated by immune effector cells such as NK cells and macrophages bearing FcγRIIIA (CD16) receptor. Previous studies reported that clinical efficacy of monoclonal antibodies can be linked to the single nucleotide polymorphism found at position 559 in cDNA of the gene encoding FcγRIIIA. This allelic polymorphism generateses the following allotypes V/V, F/V or F/F at amino acid position 158 and can affect binding of mAbs and immune cell effector function. CD16-mediated binding is most efficient with the V/V genotype, and least efficient with the F/F genotype, leading to a range of efficacy in mAb-mediated targeted therapies. Currently, many patients are not screened for CD16 heterozygosity. Nevertheless there is a clear need for a diagnostic assay that will allow estimating the allelic polymorphism of a patient undergoing treatment with monoclonal antibodies utilizing ADCC/ADCP. Here we hypothesized that the pyrosequencing might improve a screening for polymorphisms of human FcγRIIIA-158 receptor. We studied 42 normal human subjects for the incidence of V/V, F/V and F/F CD16 polymorphisms using pyrosequencing technologies and compared to nested PCR-based allele-specific restriction assay. Compared to pyrosequencing, the nested PCR-based allele-specific restriction assay was 0. 33 sensitive and 1. 0 specific in discriminating the V/V and F/F genotypes, and 0. 33 sensitive and 0. 7 specific for the V/V and F/V genotypes (Table 1). Compared to pyrosequencing, the nested PCR-based allele-specific restriction assay was relatively insensitive and not specific in distinguishing the V/V genotype from other genotypes. Since the efficacy of the mAb-based targeted immunotherapy may be highly dependent upon the CD16 polymorphism in any given individual, we propose that pyrosequencing of the CD16 receptor be routinely evaluated in all patients. Such practices might prevent patients from randomizing to receive targeted therapies to that hematological malignancies for that have little or no therapeutic potential. Table 1 V/V F/V F/F pyrosequencing 6 16 20 allele-specific restriction assay 2 23 17 sensitivity - 0.33 0.33 specificity - 0.7 1.0 Disclosures: No relevant conflicts of interest to declare.

scholarly journals Anti-EphA2 Antibodies with Distinct In Vitro Properties Have Equal In Vivo Efficacy in Pancreatic Cancer

2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Helenia Ansuini ◽  
Annalisa Meola ◽  
Zeynep Gunes ◽  
Valentina Paradisi ◽  
Monica Pezzanera ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibodies ◽  
Therapeutic Potential ◽  
Tumor Cell Line ◽  
Immunohistochemical Analysis ◽  
Receptor Activation ◽  
Rapid Identification ◽  
Antibody Treatment

The EphA2 receptor tyrosine kinase is overexpressed in a variety of human epithelial cancers and is a determinant of malignant cellular behavior in pancreatic adenocarcinoma cells. Moreover, it is expressed in tumor endothelium and its activation promotes angiogenesis. To better clarify the therapeutic potential of monoclonal antibodies (mAbs) directed to the EphA2 receptor, we generated a large number of mAbs by differential screening of phage-Ab libraries by oligonucleotide microarray technology and implemented a strategy for the rapid identification of antibodies with the desired properties. We selected two high-affinity and highly specific EphA2 monoclonal antibodies with different in vitro properties on the human pancreatic tumor cell line MiaPaCa2. One is a potent EphA2-agonistic antibody, IgG25, that promotes receptor endocytosis and subsequent degradation, and the second is a ligand antagonist, IgG28, that blocks the binding to ephrin A1 and is cross-reactive with the mouse EphA2 receptor. We measured the effect of antibody treatment on the growth of MiaPaCa2 cells orthotopically transplanted in nude mice. Both IgG25 and IgG28 had strong antitumor and antimetastatic efficacy. In vivo treatment with IgG25 determined the reduction of the EphA2 protein levels in the tumor and the phosphorylation of FAK on Tyr576 while administration of IgG28 caused a decrease in tumor vascularization as measured by immunohistochemical analysis of CD31 in tumor sections. These data show that in a pancreatic cancer model comparable therapeutic efficacy is obtained either by promoting receptor degradation or by blocking receptor activation.

scholarly journals Corrigendum: Therapeutic potential of monovalent monoclonal antibodies

Nature ◽  
1984 ◽  
Vol 309 (5968) ◽  
pp. 564-564 ◽  
Author(s):  
S. P. Cobbold ◽  
H. Waldmann
Keyword(s):  
Monoclonal Antibodies ◽  
Therapeutic Potential
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