scholarly journals An in silico method to assess antibody fragment polyreactivity

2022 ◽  
Author(s):  
Edward P Harvey ◽  
Jung-Eun Shin ◽  
Meredith A Skiba ◽  
Genevieve R Nemeth ◽  
Joseph D Hurley ◽  
...  
Keyword(s):  
Protein Sequence ◽  
Specific Binding ◽  
Antibody Fragment ◽  
Therapeutic Agents ◽  
Clinical Development ◽  
Biological Research ◽  
Type I ◽  
Polyreactive Antibodies ◽  
Quantitative Scoring ◽  
Machine Learning Models

Antibodies are essential biological research tools and important therapeutic agents, but some exhibit non-specific binding to off-target proteins and other biomolecules. Such polyreactive antibodies compromise screening pipelines, lead to incorrect and irreproducible experimental results, and are generally intractable for clinical development. We designed a set of experiments using a diverse naive synthetic camelid antibody fragment ('nanobody') library to enable machine learning models to accurately assess polyreactivity from protein sequence (AUC > 0.8). Moreover, our models provide quantitative scoring metrics that predict the effect of amino acid substitutions on polyreactivity. We experimentally tested our model's performance on three independent nanobody scaffolds, where over 90% of predicted substitutions successfully reduced polyreactivity. Importantly, the model allowed us to diminish the polyreactivity of an angiotensin II type I receptor antagonist nanobody, without compromising its pharmacological properties. We provide a companion web-server that provides a straightforward means of predicting polyreactivity and polyreactivity-reducing mutations for any given nanobody sequence.

Expression of insulin-like growth factor receptors in primary human thyroid neoplasms

1989 ◽  
Vol 121 (1) ◽  
pp. 112-120 ◽  
Author(s):  
Tohru Yashiro ◽  
Yoshito Ohba ◽  
Hitomi Murakami ◽  
Takao Obara ◽  
Toshio Tsushima ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Binding Capacity ◽  
Specific Binding ◽  
Human Thyroid ◽  
Scatchard Analysis ◽  
Type I ◽  
Single Class ◽  
Normal Tissues ◽  
Igf I ◽  
Cancer Tissues

Abstract. The presence of IGF-I receptors was demonstrated in normal and neoplastic tissues of human thyroid. Binding of [125I]IGF-I to thyroid membranes was dependent on time and temperature of incubation, and maximal binding was achieved at 4°C and 18 h of incubation. [125I] IGF-I binding was dose-dependently displaced by unlabelled IGF-I; half-maximal inhibition occurred at concentrations of 10–20 μg/l. IGF-II and insulin had relative potencies of 5 and 1% compared with IGF-I. Scatchard analysis of binding data revealed a single class of IGF-I receptors with high affinity (Ka: 1.2–8.6 × 109 1/mol) in normal thyroid tissues. Affinity cross-linking and autoradiography demonstrated the type I IGF receptors. Specific binding of [125I] IGF-I in thyroid cancer tissues (9.69 ± 2.07% per 200 μg protein; mean ± sem, N = 8) was significantly (p <0.05) higher than that in the surrounding normal tissues (3.03 ± 0.35%, N = 8). In contrast, there was no difference in the binding between adenoma tissues (4.19 ± 0.53%, N = 5) and the adjacent normal tissues (2.94 ± 0.24%, N = 5). The higher IGF-I binding in cancer tissues was due to an increase in the binding capacity without any change in the affinity. The presence of IGF-I receptors suggests a possible role of IGF-I and its receptors in the growth of thyroid cancer cells.

scholarly journals An update on the management of chronic hepatitis D

2019 ◽  
Vol 7 (6) ◽  
pp. 396-402 ◽  
Author(s):  
Pir Ahmad Shah ◽  
Saad Choudhry ◽  
Karen J Campoverde Reyes ◽  
Daryl T Y Lau
Keyword(s):  
Chronic Hepatitis ◽  
Antiviral Agents ◽  
Therapeutic Agents ◽  
Clinical Development ◽  
Severe Liver ◽  
Hepatitis D ◽  
Diagnostic Assays ◽  
Enhanced Sensitivity ◽  
At Risk Populations ◽  
Hdv Infection

Abstract Hepatitis D virus (HDV) infection is associated with severe liver-related morbidity and mortality. The prevalence of HDV is rising especially among people who abuse drugs and immigrants from endemic areas. Reliable diagnostic assays with enhanced sensitivity and specificity are essential for screening at-risk populations. Until recently, interferon has been the only treatment for hepatitis D. Its efficacy is, however, limited and it is associated with significant side effects. A number of novel antiviral agents that target various stages of the HDV life cycle show promising results. They are currently in different phases of clinical development. This review focuses on the changing epidemiology, novel therapeutic agents, and updated management of chronic hepatitis delta.

scholarly journals Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

2020 ◽  
Vol 9 (10) ◽  
pp. 3323
Author(s):  
Leila Motedayen Aval ◽  
James E. Pease ◽  
Rohini Sharma ◽  
David J. Pinato
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Therapeutics ◽  
Clinical Development ◽  
The Body ◽  
Small Subset ◽  
Type I ◽  
Principal Mechanism ◽  
Cyclic Dinucleotides ◽  
Sting Pathway

Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

scholarly journals Fucoidan from Ascophyllum nodosum Suppresses Postprandial Hyperglycemia by Inhibiting Na+/Glucose Cotransporter 1 Activity

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 485
Author(s):  
Xindi Shan ◽  
Xueliang Wang ◽  
Hao Jiang ◽  
Chao Cai ◽  
Jiejie Hao ◽  
...  
Keyword(s):  
Glucose Transport ◽  
Leptin Receptor ◽  
Specific Binding ◽  
Fasting Blood Glucose ◽  
Postprandial Hyperglycemia ◽  
Oral Glucose ◽  
Type I ◽  
Type Ii ◽  
Everted Gut Sac

We previously demonstrated that fucoidan with a type II structure inhibited postprandial hyperglycemia by suppressing glucose uptake, but the mechanism remains elusive. Here, we aimed to assess whether the effect of glucose absorption inhibition was related to the basic structure of fucoidans and preliminarily clarified the underlying mechanism. Fucoidans with type II structure and type I structure were prepared from Ascophyllumnodosum (AnF) or Laminariajaponica (LjF) and Kjellmaniellacrassifolia (KcF), respectively. The effects of various fucoidans on suppressing postprandial hyperglycemia were investigated using in vitro (Caco-2 monolayer model), semi-in vivo (everted gut sac model), and in vivo (oral glucose tolerance test, OGTT) assays. The results showed that only AnF with a type II structure, but not LjF or KcF with type I structure, could inhibit the glucose transport in the Caco-2 monolayer and everted gut sac models. A similar result was seen in the OGTT of Kunming mice and leptin receptor-deficient (db/db) mice, where only AnF could effectively inhibit glucose transport into the bloodstream. Furthermore, AnF (400 mg/kg/d) treatment decreased the fasting blood glucose, HbA1c, and fasting insulin levels, while increasing the serum glucagon-like peptide-1 (GLP-1) level in obese leptin receptor-deficient (db/db) mice. Furthermore, surface plasmon resonance (SPR) analysis revealed the specific binding of AnF to Na+/glucose cotransporter 1 (SGLT1), which indicated the effect of AnF on postprandial hyperglycemia could be due to its suppression on SGLT1 activity. Taken together, this study suggests that AnF with a type II structure can be a promising candidate for hyperglycemia treatment.

Abstract 2901: Gastric cancer antibody fragment drug-conjugates (FDCs): From concept to clinical development

2020 ◽  
Author(s):  
Mahendra P. Deonarain ◽  
Gokhan Yahioglu ◽  
ioanna Stamati ◽  
Bryan Edwards ◽  
Soraya Diez-Posada ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antibody Fragment ◽  
Clinical Development ◽  
Drug Conjugates

scholarly journals Comparison of CRISPR and Marker-Based Methods for the Engineering of Phage T7

Viruses ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 193 ◽  
Author(s):  
Aurelija M. Grigonyte ◽  
Christian Harrison ◽  
Paul R. MacDonald ◽  
Ariadna Montero-Blay ◽  
Matthew Tridgett ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Bacteriophage T7 ◽  
Type I ◽  
Type Ii ◽  
Selection Mechanism ◽  
Wild Type ◽  
Phage T7 ◽  
Fundamental Biology ◽  
Type Phage ◽  
Host Genes

With the recent rise in interest in using lytic bacteriophages as therapeutic agents, there is an urgent requirement to understand their fundamental biology to enable the engineering of their genomes. Current methods of phage engineering rely on homologous recombination, followed by a system of selection to identify recombinant phages. For bacteriophage T7, the host genes cmk or trxA have been used as a selection mechanism along with both type I and II CRISPR systems to select against wild-type phage and enrich for the desired mutant. Here, we systematically compare all three systems; we show that the use of marker-based selection is the most efficient method and we use this to generate multiple T7 tail fibre mutants. Furthermore, we found the type II CRISPR-Cas system is easier to use and generally more efficient than a type I system in the engineering of phage T7. These results provide a foundation for the future, more efficient engineering of bacteriophage T7.

scholarly journals COVID-19 Drug Discovery Using Intensive Approaches

2020 ◽  
Vol 21 (8) ◽  
pp. 2839 ◽  
Author(s):  
Ayumu Asai ◽  
Masamitsu Konno ◽  
Miyuki Ozaki ◽  
Chihiro Otsuka ◽  
Andrea Vecchione ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Rna Viruses ◽  
Drug Repurposing ◽  
Global Scale ◽  
Therapeutic Agents ◽  
Clinical Development ◽  
World Health ◽  
Antiviral Therapies ◽  
The World ◽  
Health Organization

Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.

‘Small’-proteoglycan: collagen interactions: Keratan sulphate proteoglycan associates with rabbit corneal collagen fibrils at the ‘a’ and ‘c’ bands

1985 ◽  
Vol 5 (9) ◽  
pp. 765-774 ◽  
Author(s):  
J. E. Scott ◽  
M. Haigh
Keyword(s):  
Binding Sites ◽  
Type I Collagen ◽  
Specific Binding ◽  
Corneal Stroma ◽  
Collagen Fibrils ◽  
Type I ◽  
Keratan Sulphate ◽  
Protein Rich ◽  
Small Proteoglycan ◽  
Corneal Collagen

l. Proteoglycans (PGs) in rabbit corneal stroma and mouse sclera have been stained for electron microscopy with Cupromeronic blue in a critical electrolyte concentration (CEC) mode, with and without prior digestion of the tissue by keratanase or chondroitinase ABC to remove the keratan sulphate (KS) or chondroitin-dermatan sulphates (CS or DS) respectively.2. Two classes of PGs, located orthogonally to the corneal collagen fibrils at either the ‘step’ (band ‘a’ or ‘c’) or gap zone (band ‘d’ or ‘e’) are shown to be KS-PGs or DS-PGs respectively. Four separate and specific PG binding sites on Type I collagen fibrils have thus been identified.3. Rabbit corneal KS and DS PGs each contain two kinds of PG (Gregory JD, Coster L & Damle SP (1982) J. Biol. Chem.257, 6965–6970). We propose that each ‘small’ protein-rich PG is associated with a specific binding site on the collagen fibril.

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