scholarly journals Recognition of Dimeric Lewis X by Anti-Dimeric Lex Antibody SH2

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 538
Author(s):  
Sinthuja Jegatheeswaran ◽  
Ari Asnani ◽  
Adam Forman ◽  
Jenifer L. Hendel ◽  
Christopher J. Moore ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Bovine Serum Albumin ◽  
Competitive Inhibition ◽  
Cancer Therapeutics ◽  
Carbohydrate Antigen ◽  
Autoimmune Response ◽  
Lewis X ◽  
Recognition Element ◽  
Anti Cancer ◽  
Lex Antigen

The carbohydrate antigen dimeric Lewis X (DimLex), which accumulates in colonic and liver adenocarcinomas, is a valuable target to develop anti-cancer therapeutics. Using the native DimLex antigen as a vaccine would elicit an autoimmune response against the Lex antigen found on normal, healthy cells. Thus, we aim to study the immunogenic potential of DimLex and search internal epitopes displayed by DimLex that remain to be recognized by anti-DimLex monoclonal antibodies (mAbs) but no longer possess epitopes recognized by anti-Lex mAbs. In this context, we attempted to map the epitope recognized by anti-DimLex mAb SH2 by titrations and competitive inhibition experiments using oligosaccharide fragments of DimLex as well as Lex analogues. We compare our results with that reported for anti-Lex mAb SH1 and anti-polymeric Lex mAbs 1G5F6 and 291-2G3-A. While SH1 recognizes an epitope localized to the non-reducing end Lex trisaccharide, SH2, 1G5F6, and 291-2G3-A have greater affinity for DimLex conjugates than for Lex conjugates. We show, however, that the Lex trisaccharide is still an important recognition element for SH2, which (like 1G5F6 and 291-2G3-A) makes contacts with all three sugar units of Lex. In contrast to mAb SH1, anti-polymeric Lex mAbs make contact with the GlcNAc acetamido group, suggesting that epitopes extend further from the non-reducing end Lex. Results with SH2 show that this epitope is only recognized when DimLex is presented by glycoconjugates. We have reported that DimLex adopts two conformations around the β-d-GlcNAc-(1→3)-d-Gal bond connecting the Lex trisaccharides. We propose that only one of these conformations is recognized by SH2 and that this conformation is favored when the hexasaccharide is presented as part of a glycoconjugate such as DimLex-bovine serum albumin (DimLex-BSA). Proper presentation of the oligosaccharide candidate via conjugation to a protein or lipid is essential for the design of an anti-cancer vaccine or immunotherapeutic based on DimLex.

scholarly journals Physical connectivity mapping by circular permutation of human telomerase RNA reveals new regions critical for activity and processivity

2015 ◽  
pp. MCB.00794-15 ◽  
Author(s):  
Melissa A. Mefford ◽  
David C. Zappulla
Keyword(s):  
Cancer Therapeutics ◽  
Telomerase Activity ◽  
Circular Permutation ◽  
Telomerase Rna ◽  
Recognition Element ◽  
Circular Permutations ◽  
Anti Cancer ◽  
Human Telomerase ◽  
First Time

Telomerase is a specialized ribonucleoprotein complex that extends the 3’ ends of chromosomes to counteract telomere shortening. However, increased telomerase activity is associated with ∼90% of human cancers. The telomerase enzyme minimally requires an RNA (hTR) and a specialized reverse transcriptase protein (TERT) for activityin vitro. Understanding the structure-function relationships within hTR has important implications for human disease. For the first time, we have tested the physical-connectivity requirements in the 451-nucleotide hTR RNA using circular permutations, which reposition the 5’ and 3’ ends. Our extensivein vitroanalysis identified three classes of hTR circular permutants with altered function. First, circularly permuting 3’ of the template causes specific defects in repeat-addition processivity, revealing that the template-recognition element found in ciliates is conserved in human telomerase RNA. Second, seven circular permutations residing within the catalytically important core and CR4/5 domains completely abolish telomerase activity, unveiling mechanistically critical portions of these domains. Third, several circular permutations between the core and CR4/5 significantly increase telomerase activity. Our extensive circular permutation results provide insights into the architecture and coordination of human hTR and highlight where the RNA could be targeted for the development of anti-aging and anti-cancer therapeutics.

scholarly journals Selection and Characterization of YKL-40-Targeting Monoclonal Antibodies from Human Synthetic Fab Phage Display Libraries

2020 ◽  
Vol 21 (17) ◽  
pp. 6354
Author(s):  
Kyungjae Kang ◽  
Kicheon Kim ◽  
Se-Ra Lee ◽  
Yoonji Kim ◽  
Joo Eon Lee ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Phage Display ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Migration Assay ◽  
Synthetic Antibody ◽  
Phage Display Libraries ◽  
Anti Cancer

YKL-40, also known as chitinase-3-like 1 (CHI3L1), is a glycoprotein that is expressed and secreted by various cell types, including cancers and macrophages. Due to its implications for and upregulation in a variety of diseases, including inflammatory conditions, fibrotic disorders, and tumor growth, YKL-40 has been considered as a significant therapeutic biomarker. Here, we used a phage display to develop novel monoclonal antibodies (mAbs) targeting human YKL-40 (hYKL-40). Human synthetic antibody phage display libraries were panned against a recombinant hYKL-40 protein, yielding seven unique Fabs (Antigen-binding fragment), of which two Fabs (H1 and H2) were non-aggregating and thermally stable (75.5 °C and 76.5 °C, respectively) and had high apparent affinities (KD = 2.3 nM and 4.0 nM, respectively). Reformatting the Fabs into IgGs (Immunoglobulin Gs) increased their apparent affinities (notably, for H1 and H2, KD = 0.5 nM and 0.3 nM, respectively), presumably due to the effects of avidity, with little change to their non-aggregation property. The six anti-hYKL-40 IgGs were analyzed using a trans-well migration assay in vitro, revealing that three clones (H1, H2, and H4) were notably effective in reducing cell migration from both A549 and H460 lung cancer cell lines. The three clones were further analyzed in an in vivo animal test that assessed their anti-cancer activities, demonstrating that the tumor area and the number of tumor nodules were significantly reduced in the lung tissues treated with H1 (IgG). Given its high affinity and desirable properties, we expect that the H1 anti-hYKL-40 mAb will be a suitable candidate for developing anti-cancer therapeutics.

Animal Venoms have Potential to Treat Cancer

2019 ◽  
Vol 18 (30) ◽  
pp. 2555-2566 ◽  
Author(s):  
Bhaswati Chatterjee
Keyword(s):  
Cancer Therapeutics ◽  
Sea Anemones ◽  
Anticancer Activities ◽  
Inhibition Of Proliferation ◽  
Cycle Arrest ◽  
Venomous Animals ◽  
Anti Cancer ◽  
Cancerous Cells ◽  
Animal Venoms ◽  
Proteins And Peptides

The resistance to chemotherapeutics by the cancerous cells has made its treatment more complicated. Animal venoms have emerged as an alternative strategy for anti-cancer therapeutics. Animal venoms are cocktails of complex bioactive chemicals mainly disulfide-rich proteins and peptides with diverse pharmacological actions. The components of venoms are specific, stable, and potent and have the ability to modify their molecular targets thus making them good therapeutics candidates. The isolation of cancer-specific components from animal venoms is one of the exciting strategies in anti-cancer research. This review highlights the identified venom peptides and proteins from different venomous animals like snakes, scorpions, spiders, bees, wasps, snails, toads, frogs and sea anemones and their anticancer activities including inhibition of proliferation of cancer cells, their invasion, cell cycle arrest, induction of apoptosis and the identification of involved signaling pathways.

The Applications of Targeting Anti-Cancer Agents in Cancer Therapeutics

2015 ◽  
Vol 15 (7) ◽  
pp. 869-880 ◽  
Author(s):  
Guang-Chun Sun ◽  
X Yang ◽  
Yan Yu ◽  
Dai-Wei Zhao
Keyword(s):  
Cancer Therapeutics ◽  
Anti Cancer

Innovatory role of nanomaterials as bio-tools for treatment of cancer

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Khuram Shahzad Ahmad ◽  
Muntaha Talat ◽  
Shaan Bibi Jaffri ◽  
Neelofer Shaheen
Keyword(s):  
Cancer Treatment ◽  
Cancer Therapeutics ◽  
Physicochemical Characteristics ◽  
Global Scale ◽  
Current Review ◽  
Anti Cancer ◽  
Different Types ◽  
Cancerous Cells

AbstractConventional treatment modes like chemotherapy, thermal and radiations aimed at cancerous cells eradication are marked by destruction pointing the employment of nanomaterials as sustainable and auspicious materials for saving human lives. Cancer has been deemed as the second leading cause of death on a global scale. Nanomaterials employment in cancer treatment is based on the utilization of their inherent physicochemical characteristics in addition to their modification for using as nano-carriers and nano-vehicles eluted with anti-cancer drugs. Current work has reviewed the significant role of different types of nanomaterials in cancer therapeutics and diagnostics in a systematic way. Compilation of review has been done by analyzing voluminous investigations employing ERIC, MEDLINE, NHS Evidence and Web of Science databases. Search engines used were Google scholar, Jstore and PubMed. Current review is suggestive of the remarkable performance of nanomaterials making them candidates for cancer treatment for substitution of destructive treatment modes through investigation of their physicochemical characteristics, utilization outputs and long term impacts in patients.

scholarly journals Surface-Initiated Atom Transfer Polymerized Anionic Corona on Gold Nanoparticles for Anti-Cancer Therapy

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 261
Author(s):  
Wei Mao ◽  
Sol Lee ◽  
Ji Un Shin ◽  
Hyuk Sang Yoo
Keyword(s):  
Gold Nanoparticles ◽  
Transfection Efficiency ◽  
Cancer Therapeutics ◽  
Atom Transfer ◽  
Layer By Layer ◽  
Dependent Manner ◽  
Metallic Particles ◽  
Anti Cancer

Surface initiated atom transfer radical polymerization (SI-ATRP) documented a simple but efficient technique to grow a dense polymer layer on any surface. Gold nanoparticles (AuNPs) give a broad surface to immobilize sulfhyryl group-containing initiators for SI-ATRP; in addition, AuNPs are the major nanoparticulate carriers for delivery of anti-cancer therapeutics, since they are biocompatible and bioinert. In this work, AuNPs with a disulfide initiator were polymerized with sulfoethyl methacrylate by SI-ATRP to decorate the particles with anionic corona, and branched polyethyeleneimine (PEI) and siRNA were sequentially layered onto the anionic corona of AuNP by electrostatic interaction. The in vitro anti-cancer effect confirmed that AuNP with anionic corona showed higher degrees of apoptosis as well as suppression of the oncogene expression in a siRNA dose-dependent manner. The in vivo study of tumor-bearing nude mice revealed that mice treated with c-Myc siRNA-incorporated AuNPs showed dramatically decreased tumor size in comparison to those with free siRNA for 4 weeks. Furthermore, histological examination and gene expression study revealed that the decorated AuNP significantly suppressed c-Myc expression. Thus, we envision that the layer-by-layer assembly on the anionic brushes can be potentially used to incorporate nucleic acids onto metallic particles with high transfection efficiency.

Stress responses as master keys to epigenomic changes in transcriptome and metabolome for cancer etiology and therapeutics

2021 ◽  
Author(s):  
Atanu Mondal ◽  
Apoorva Bhattacharya ◽  
Vipin Singh ◽  
Shruti Pandita ◽  
Albino Bacolla ◽  
...  
Keyword(s):  
Stress Response ◽  
Cancer Cells ◽  
Stress Responses ◽  
Current Knowledge ◽  
Cancer Therapeutics ◽  
Molecular Architecture ◽  
Cancer Etiology ◽  
Treatment Scenario ◽  
Anti Cancer ◽  
Novel Therapeutic Strategies

From initiation through progression, cancer cells are subjected to a magnitude of endogenous and exogenous stresses, which aid in their neoplastic transformation. Exposure to these classes of stress induces imbalance in cellular homeostasis and, in response, cancer cells employ informative adaptive mechanisms to rebalance biochemical processes that facilitate survival and maintain their existence. Different kinds of stress stimuli trigger epigenetic alterations in cancer cells, which leads to changes in their transcriptome and metabolome, ultimately resulting in suppression of growth inhibition or induction of apoptosis. Whether cancer cells show a protective response to stress or succumb to cell death depends on the type of stress and duration of exposure. A thorough understanding of epigenetic and molecular architecture of cancer cell stress response pathways can unveil a plethora of information required to develop novel anti-cancer therapeutics. The present view highlights current knowledge about alterations in epigenome and transcriptome of cancer cells as a consequence of exposure to different physicochemical stressful stimuli such as reactive oxygen species (ROS), hypoxia, radiation, hyperthermia, genotoxic agents, and nutrient deprivation. Currently, an anti-cancer treatment scenario involving the imposition of stress on target cancer cells is gaining traction to augment or even replace conventional therapeutic regimens. Therefore, a comprehensive understanding of stress response pathways is crucial for devising and implementing novel therapeutic strategies.

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