scholarly journals Biophysical properties of the clinical-stage antibody landscape

2017 ◽  
Vol 114 (5) ◽  
pp. 944-949 ◽  
Author(s):  
Tushar Jain ◽  
Tingwan Sun ◽  
Stéphanie Durand ◽  
Amy Hall ◽  
Nga Rewa Houston ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Clinical Stage ◽  
Biological Properties ◽  
Therapeutic Use ◽  
Amino Acid Sequences ◽  
High Potency ◽  
Biological Drugs ◽  
Biophysical Property ◽  
Drug Candidates ◽  
Practical Guidelines

Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of “developability.” Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.

scholarly journals Electrospun Nanofibrous Membranes for Tissue Engineering and Cell Growth

2021 ◽  
Vol 11 (15) ◽  
pp. 6929
Author(s):  
Ewin Tanzli ◽  
Andrea Ehrmann
Keyword(s):  
Tissue Engineering ◽  
Cell Growth ◽  
Polymer Blends ◽  
Mammalian Cells ◽  
Biological Properties ◽  
Specific Substrate ◽  
Electrospun Nanofiber ◽  
Materials Used ◽  
Nanofiber Mats ◽  
Surface Morphologies

In biotechnology, the field of cell cultivation is highly relevant. Cultivated cells can be used, for example, for the development of biopharmaceuticals and in tissue engineering. Commonly, mammalian cells are grown in bioreactors, T-flasks, well plates, etc., without a specific substrate. Nanofibrous mats, however, have been reported to promote cell growth, adhesion, and proliferation. Here, we give an overview of the different attempts at cultivating mammalian cells on electrospun nanofiber mats for biotechnological and biomedical purposes. Starting with a brief overview of the different electrospinning methods, resulting in random or defined fiber orientations in the nanofiber mats, we describe the typical materials used in cell growth applications in biotechnology and tissue engineering. The influence of using different surface morphologies and polymers or polymer blends on the possible application of such nanofiber mats for tissue engineering and other biotechnological applications is discussed. Polymer blends, in particular, can often be used to reach the required combination of mechanical and biological properties, making such nanofiber mats highly suitable for tissue engineering and other biotechnological or biomedical cell growth applications.

scholarly journals E2F activity is regulated by cell cycle-dependent changes in subcellular localization.

1997 ◽  
Vol 17 (12) ◽  
pp. 7268-7282 ◽  
Author(s):  
R Verona ◽  
K Moberg ◽  
S Estes ◽  
M Starz ◽  
J P Vernon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Subcellular Localization ◽  
Nuclear Localization ◽  
Mammalian Cells ◽  
Critical Role ◽  
Biological Properties ◽  
Dependent Manner ◽  
Restriction Point ◽  
Cycle Dependent ◽  
Almost All

E2F directs the cell cycle-dependent expression of genes that induce or regulate the cell division process. In mammalian cells, this transcriptional activity arises from the combined properties of multiple E2F-DP heterodimers. In this study, we show that the transcriptional potential of individual E2F species is dependent upon their nuclear localization. This is a constitutive property of E2F-1, -2, and -3, whereas the nuclear localization of E2F-4 is dependent upon its association with other nuclear factors. We previously showed that E2F-4 accounts for the majority of endogenous E2F species. We now show that the subcellular localization of E2F-4 is regulated in a cell cycle-dependent manner that results in the differential compartmentalization of the various E2F complexes. Consequently, in cycling cells, the majority of the p107-E2F, p130-E2F, and free E2F complexes remain in the cytoplasm. In contrast, almost all of the nuclear E2F activity is generated by pRB-E2F. This complex is present at high levels during G1 but disappears once the cells have passed the restriction point. Surprisingly, dissociation of this complex causes little increase in the levels of nuclear free E2F activity. This observation suggests that the repressive properties of the pRB-E2F complex play a critical role in establishing the temporal regulation of E2F-responsive genes. How the differential subcellular localization of pRB, p107, and p130 contributes to their different biological properties is also discussed.

scholarly journals Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations

2018 ◽  
Vol 9 ◽  
pp. 1050-1074 ◽  
Author(s):  
Jaison Jeevanandam ◽  
Ahmed Barhoum ◽  
Yen S Chan ◽  
Alain Dufresne ◽  
Michael K Danquah
Keyword(s):  
Risk Assessment ◽  
Nanostructured Materials ◽  
Mammalian Cells ◽  
Size Composition ◽  
Biological Properties ◽  
Industrial Applications ◽  
Specific Knowledge ◽  
Naturally Occurring ◽  
Physical Chemical ◽  
Toxic Reactions

Nanomaterials (NMs) have gained prominence in technological advancements due to their tunable physical, chemical and biological properties with enhanced performance over their bulk counterparts. NMs are categorized depending on their size, composition, shape, and origin. The ability to predict the unique properties of NMs increases the value of each classification. Due to increased growth of production of NMs and their industrial applications, issues relating to toxicity are inevitable. The aim of this review is to compare synthetic (engineered) and naturally occurring nanoparticles (NPs) and nanostructured materials (NSMs) to identify their nanoscale properties and to define the specific knowledge gaps related to the risk assessment of NPs and NSMs in the environment. The review presents an overview of the history and classifications of NMs and gives an overview of the various sources of NPs and NSMs, from natural to synthetic, and their toxic effects towards mammalian cells and tissue. Additionally, the types of toxic reactions associated with NPs and NSMs and the regulations implemented by different countries to reduce the associated risks are also discussed.

Development and Advances of Drugs for Cancer Theranostics – PART-IV

2021 ◽  
Vol 21 (18) ◽  
pp. 1644-1644
Author(s):  
Lian-Shun Feng
Keyword(s):  
Drug Discovery ◽  
Side Effects ◽  
Anticancer Activity ◽  
Anticancer Drug ◽  
Anticancer Agents ◽  
Drug Repurposing ◽  
Biological Properties ◽  
Drug Candidates ◽  
Pharmacokinetic Profiles ◽  
Hybrid Molecules

Cancer, a highly heterogeneous disease at intra/inter patient levels, is one of the most serious threats to human health across the world [1, 2]. Notwithstanding the noteworthy advances in its treat-ment, the morbidity and mortality of cancer are projected to grow for a long period, and the global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020 [3]. Accordingly, there is a constant need to explore novel anticancer agents. <p> There are several strategies to discover novel anticancer candidates: (1) new lead hits or candidates from natural resources [4] whichexhibit various biological properties and are a rich source of com-pounds in drug discovery due to the structural and mechanistic diversity, and more than 60% anti-cancer agents can be traced to a natural product; (2) Molecular hybridization is one of the most prom-ising strategies for the discovery of novel anticancer drug candidates since hybrid molecules have the potential to bind multiple targets or to enhance the effect through acting with another bio-target or to counterbalance the side effects caused by the other part of the hybrid [5]; (3) Dimerization is a useful tool to develop novel anticancer drug candidates with enhanced biological activity, reduced side effects and improved pharmacokinetic profiles [6]; (4) Drug repurposing strategy is is an attractive strategy and has been approved, along with non-anticancer macrolide drugs for the treatment of cancer, for anticancer drug discovery since toxicity and pharmacokinetic profiles have already been estab-lished [7]. <p> Heterocycles coumarin, β-lactone, macrolide and triazole are useful anticancer pharmacophores since their derivatives could exert the anticancer activity through diverse mechanisms, inclusive of inhibition of aromatase, carbonic anhydrase, ki-nase, P-glycoprotein, sulfatase, telomerase, vascular endothelial growth factor receptor 2 and tubulin [8-11]. In particular, nat-ural-derived coumarin, β-lactone and macrolide derivatives are important sources of new anticancer lead hits/candidates; mac-rolide repurposed drugs can circumvent high cost and long-time associated with traditional drug discovery strategies; couma-rin, β-lactone and macrolide hybrids as well as bis-triazole compounds have the potential to enhance the anticancer activity, overcome drug resistance, reduce the side effects and improve pharmacokinetic profiles.

Improved ligand-binding- and signaling-competent human NK2R yields in yeast using a chimera with the rat NK2R C-terminus enable NK2R-G protein signaling platform

2019 ◽  
Vol 32 (10) ◽  
pp. 459-469 ◽  
Author(s):  
Abhinav R Jain ◽  
Zachary T Britton ◽  
Chester E Markwalter ◽  
Anne S Robinson
Keyword(s):  
Protein Engineering ◽  
Ligand Binding ◽  
G Protein ◽  
Mammalian Cells ◽  
Protein Signaling ◽  
Ligand Interaction ◽  
Downstream Signaling ◽  
Drug Candidates ◽  
C Terminus ◽  
Engineering Strategy

Abstract The tachykinin 2 receptor (NK2R) plays critical roles in gastrointestinal, respiratory and mental disorders and is a well-recognized target for therapeutic intervention. To date, therapeutics targeting NK2R have failed to meet regulatory agency approval due in large part to the limited characterization of the receptor-ligand interaction and downstream signaling. Herein, we report a protein engineering strategy to improve ligand-binding- and signaling-competent human NK2R that enables a yeast-based NK2R signaling platform by creating chimeras utilizing sequences from rat NK2R. We demonstrate that NK2R chimeras incorporating the rat NK2R C-terminus exhibited improved ligand-binding yields and downstream signaling in engineered yeast strains and mammalian cells, where observed yields were better than 4-fold over wild type. This work builds on our previous studies that suggest exchanging the C-termini of related and well-expressed family members may be a general protein engineering strategy to overcome limitations to ligand-binding and signaling-competent G protein-coupled receptor yields in yeast. We expect these efforts to result in NK2R drug candidates with better characterized signaling properties.

In vitro biological properties and predicted DNA–BSA interaction of three new dicyanidoargentate(i)-based complexes: synthesis and characterization

2018 ◽  
Vol 42 (6) ◽  
pp. 4679-4692 ◽  
Author(s):  
Ahmet Karadağ ◽  
Nesrin Korkmaz ◽  
Ali Aydın ◽  
Şaban Tekin ◽  
Yusuf Yanar ◽  
...  
Keyword(s):  
Biological Activity ◽  
Biological Properties ◽  
Synthesis And Characterization ◽  
Drug Candidates ◽  
Bsa Interaction

The synthesis, characterization and biological activity of three novel dicyanidoargentate(i)-based complexes are reported. The in vitro results show that these complexes may be potent antiproliferative drug candidates.

scholarly journals Safety and Pharmacokinetics of a Four Monoclonal Antibody Combination against Botulinum C and D Neurotoxins

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Doris M. Snow ◽  
Kathryn Riling ◽  
Angie Kimbler ◽  
Yero Espinoza ◽  
David Wong ◽  
...  
Keyword(s):  
Phase 1 ◽  
Human Study ◽  
Amino Acid Sequences ◽  
High Potency ◽  
Human Mabs ◽  
Tier 1 ◽  
Physical Examinations ◽  
Human Igg1 ◽  
Antidrug Antibodies

ABSTRACT Botulism is caused by botulinum neurotoxin (BoNT), the most poisonous substance known. BoNTs are also classified as tier 1 biothreat agents due to their high potency and lethality. The existence of seven BoNT serotypes (A to G), which differ by 35% to 68% in amino acid sequences, necessitates the development of serotype-specific countermeasures. We present results of a phase 1 clinical study of an anti-toxin to BoNT serotypes C and D, NTM-1634, which consists of an equimolar mixture of four fully human IgG1 monoclonal antibodies (MAbs), each binding to nonoverlapping epitopes on BoNT serotypes C and D, resulting in potent toxin neutralization in rodents. This first in-human study evaluated the safety and pharmacokinetics of escalating doses of NTM-1634 administered intravenously to healthy adults. Three cohorts of eight healthy subjects received single intravenous doses of NTM-1634 at 0.33 mg/kg, 0.66 mg/kg, or 1 mg/kg or placebo. Follow-up examinations and pharmacokinetics evaluations were continued up to 121 days postinfusion. Subjects were monitored by using physical examinations, hematology and chemistry blood tests, and electrocardiograms. Pharmacokinetics parameters were estimated using noncompartmental methods. The results demonstrated that the materials were safe and well tolerated with the expected half-lives for human MAbs and with minimal antidrug antibodies detected over the dose ranges and duration of the study. (This study has been registered at ClinicalTrials.gov under identifier NCT03046550.)

P251 THERAPEUTIC USE OF A CLINICAL STAGE CCR2 INHIBITOR, CCX872, IMPROVES OBESITY ASSOCIATED STEATOHEPATITIS IN MICE

2014 ◽  
Vol 60 (1) ◽  
pp. S149
Author(s):  
R. Parker ◽  
M.J. Walters ◽  
L. Ertle ◽  
K. Ebsworth ◽  
J. Tan ◽  
...  
Keyword(s):  
Clinical Stage ◽  
Therapeutic Use

Targeting motifs and functional parameters governing the assembly of connexins into gap junctions

2000 ◽  
Vol 349 (1) ◽  
pp. 281-287 ◽  
Author(s):  
Patricia E. M. MARTIN ◽  
James STEGGLES ◽  
Claire WILSON ◽  
Shoeb AHMAD ◽  
W. Howard EVANS
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Gap Junctions ◽  
Gap Junction ◽  
Mammalian Cells ◽  
Fluorescent Protein ◽  
Lucifer Yellow ◽  
Amino Acid Sequences ◽  
Amino Acid Residues ◽  
Green Fluorescent

To study the assembly of gap junctions, connexin-green-fluorescent-protein (Cx-GFP) chimeras were expressed in COS-7 and HeLa cells. Cx26- and Cx32-GFP were targeted to gap junctions where they formed functional channels that transferred Lucifer Yellow. A series of Cx32-GFP chimeras, truncated from the C-terminal cytoplasmic tail, were studied to identify amino acid sequences governing targeting from intracellular assembly sites to the gap junction. Extensive truncation of Cx32 resulted in failure to integrate into membranes. Truncation of Cx32 to residue 207, corresponding to removal of most of the 78 amino acids on the cytoplasmic C-terminal tail, led to arrest in the endoplasmic reticulum and incomplete oligomerization. However, truncation to amino acid 219 did not impair Cx oligomerization and connexon hemichannels were targeted to the plasma membrane. It was concluded that a crucial gap-junction targeting sequence resides between amino acid residues 207 and 219 on the cytoplasmic C-terminal tail of Cx32. Studies of a Cx32E208K mutation identified this as one of the key amino acids dictating targeting to the gap junction, although oligomerization of this site-specific mutation into hexameric hemichannels was relatively unimpaired. The studies show that expression of these Cx-GFP constructs in mammalian cells allowed an analysis of amino acid residues involved in gap-junction assembly.

Bauhinia Kunitz-type proteinase inhibitors: structural characteristics and biological properties

2008 ◽  
Vol 389 (8) ◽  
Author(s):  
Maria Luiza Vilela Oliva ◽  
Misako Uemura Sampaio
Keyword(s):  
Proteinase Inhibitors ◽  
Structural Characteristics ◽  
Biological Properties ◽  
Therapeutic Use ◽  
Biological Processes ◽  
Functional Characteristics ◽  
Kunitz Type ◽  
Synthetic Derivatives

AbstractPlant proteinase inhibitors are involved in the regulation of the activity of many proteinases and, in consequence, in biological processes driven by proteolysis. In this review, we summarize recent results on the activity of nativeBauhiniainhibitors and synthetic derivatives. Structural and functional characteristics and the potential therapeutic use of these inhibitors are also discussed.

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