In Vivo Intrathecal Tracer Dispersion in Cynomolgus Monkey Validates Wide Biodistribution Along Neuraxis

2020 ◽  
Vol 67 (4) ◽  
pp. 1122-1132 ◽  
Author(s):  
Kevin Tangen ◽  
Ivan Nestorov ◽  
Ajay Verma ◽  
Jenna Sullivan ◽  
Robert W. Holt ◽  
...  
Keyword(s):  
Cynomolgus Monkey ◽  
Tracer Dispersion

scholarly journals Utilization of the chronic atrioventricular block cynomolgus monkey as an in vivo model to evaluate drug interaction-associated torsade de pointes

2020 ◽  
Vol 142 (4) ◽  
pp. 172-175 ◽  
Author(s):  
Ai Goto ◽  
Kengo Sakamoto ◽  
Mihoko Hagiwara-Nagasawa ◽  
Ryuichi Kambayashi ◽  
Koki Chiba ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Atrioventricular Block ◽  
Cynomolgus Monkey ◽  
Torsade De Pointes ◽  
In Vivo Model

In vitro culture of cynomolgus monkey embryos beyond early gastrulation

Science ◽  
2019 ◽  
Vol 366 (6467) ◽  
pp. eaax7890 ◽  
Author(s):  
Huaixiao Ma ◽  
Jinglei Zhai ◽  
Haifeng Wan ◽  
Xiangxiang Jiang ◽  
Xiaoxiao Wang ◽  
...  
Keyword(s):  
In Vitro Culture ◽  
Cynomolgus Monkey ◽  
Primordial Germ Cells ◽  
Lineage Specification ◽  
Single Cell Rna Sequencing ◽  
Human Embryogenesis ◽  
Key Events ◽  
Anterior Posterior

Gastrulation is a key event in embryonic development when the germ layers are specified and the basic animal body plan is established. The complexities of primate gastrulation remain a mystery because of the difficulties in accessing primate embryos at this stage. Here, we report the establishment of an in vitro culture (IVC) system that supports the continuous development of cynomolgus monkey blastocysts beyond early gastrulation up to 20 days after fertilization. The IVC embryos highly recapitulated the key events of in vivo early postimplantation development, including segregation of the epiblast and hypoblast, formation of the amniotic and yolk sac cavities, appearance of the primordial germ cells, and establishment of the anterior-posterior axis. Single-cell RNA-sequencing analyses of the IVC embryos provide information about lineage specification during primate early postimplantation development. This system provides a platform with which to explore the characteristics and mechanisms of early postimplantation embryogenesis in primates with possible conservation of cell movements and lineages in human embryogenesis.

scholarly journals Interspecies Variation in NCMN-O-Demethylation in Liver Microsomes from Various Species

Molecules ◽  
2019 ◽  
Vol 24 (15) ◽  
pp. 2765
Author(s):  
Ziru Dai ◽  
Guibo Sun ◽  
Jiada Yang ◽  
Jie Hou ◽  
Ping Zhou ◽  
...  
Keyword(s):  
Cynomolgus Monkey ◽  
Liver Microsomes ◽  
Specific Inhibitor ◽  
Intrinsic Clearance ◽  
Beagle Dog ◽  
Interspecies Variation ◽  
Human Cytochrome ◽  
Practical Tool ◽  
Cytochrome P450 1A

NCMN (N-(3-carboxy propyl)-4-methoxy-1,8-naphthalimide), a newly developed ratiometric two-photon fluorescent probe for human Cytochrome P450 1A (CYP1A), shows the best combination of specificity and reactivity for real-time detection of the enzymatic activities of CYP1A in complex biological systems. This study aimed to investigate the interspecies variation in NCMN-O-demethylation in commercially available liver microsomes from human, mouse, rat, beagle dog, minipig and cynomolgus monkey. Metabolite profiling demonstrated that NCMN could be O-demethylated in liver microsomes from all species but the reaction rate varied considerably. CYP1A was the major isoform involved in NCMN-O-demethylation in all examined liver microsomes based on the chemical inhibition assays. Furafylline, a specific inhibitor of mammalian CYP1A, displayed differential inhibitory effects on NCMN-O-demethylation in all tested species. Kinetic analyses demonstrated that NCMN-O-demethylation in liver microsomes form rat, minipig and cynomolgus monkey followed biphasic kinetics, while in liver microsomes form human, mouse and beagle dog obeyed Michaelis-Menten kinetics, the kinetic parameters from various species are much varied, while NCMN-O-demethylation in MLM exhibited the highest similarity of specificity, kinetic behavior and intrinsic clearance as that in HLM. These findings will be very helpful for the rational use of NCMN as a practical tool to decipher the functions of mammalian CYP1A or to study CYP1A associated drug-drug interactions in vivo.

scholarly journals Preexisting Antibodies to an F(ab′)2Antibody Therapeutic and Novel Method for Immunogenicity Assessment

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Jane Ruppel ◽  
Ann Brady ◽  
Rebecca Elliott ◽  
Cecilia Leddy ◽  
Marco Palencia ◽  
...  
Keyword(s):  
Cynomolgus Monkey ◽  
Drug Exposure ◽  
Therapeutic Antibodies ◽  
Competition Assay ◽  
Safety And Efficacy ◽  
Immunogenicity Assessment ◽  
Novel Method ◽  
Assay Methods ◽  
Potential Antitumor

Anti-therapeutic antibodies (ATAs) may impact drug exposure and activity and induce immune complex mediated toxicity; therefore the accurate measurement of ATA is important for the analysis of drug safety and efficacy. Preexisting ATAs to the hinge region of anti-Delta like ligand 4 (anti-DLL4) F(ab′)2, a potential antitumor therapeutic, were detected in cynomolgus monkey serum, which presented a challenge in developing assays for detecting treatment induced ATA. A total ATA assay was developed using a bridging ELISA that detected both anti-CDR and anti-framework ATA including anti-hinge reactivity. A competition assay that could detect 500 ng/mL of anti-CDR ATA in the presence of preexisting ATA was also developed to determine ATA specific to the anti-DLL4 F(ab′)2CDR using anti-DLL4 F(ab′)2and a control F(ab′)2. We used these assay methods in a cynomolgus monkey in vivo study to successfully evaluate total and anti-CDR ATA. The preexisting anti-hinge reactivity was also observed to a lesser extent in human serum, and a similar approach could be applied for specific immunogenicity assessment in clinical trials.

Detection of drug specific circulating immune complexes from in vivo cynomolgus monkey serum samples

2015 ◽  
Vol 416 ◽  
pp. 124-136 ◽  
Author(s):  
Piotr Pierog ◽  
Murli Krishna ◽  
Aaron Yamniuk ◽  
Anil Chauhan ◽  
Binodh DeSilva
Keyword(s):  
Immune Complexes ◽  
Cynomolgus Monkey ◽  
Circulating Immune Complexes ◽  
Serum Samples

In vivo dosimetry of ethylene oxide and propylene oxide in the cynomolgus monkey

1996 ◽  
Vol 357 (1-2) ◽  
pp. 17-23 ◽  
Author(s):  
R. Couch ◽  
L. Ehrenberg ◽  
A.-L. Magnusson ◽  
R. Nilsson ◽  
M.E. de la Rosa ◽  
...  
Keyword(s):  
Ethylene Oxide ◽  
Propylene Oxide ◽  
Cynomolgus Monkey ◽  
In Vivo Dosimetry

DNA sequence analysis of spontaneous and n-ethyl-n-nitrosourea-lnducedhprt mutations arising in vivo in cynomolgus monkey t-lymphocytes

1992 ◽  
Vol 20 (2) ◽  
pp. 96-105 ◽  
Author(s):  
P. R. Harbach ◽  
A. L. Filipunas ◽  
Y. Wang ◽  
C. S. Aaron
Keyword(s):  
Sequence Analysis ◽  
T Lymphocytes ◽  
Dna Sequence ◽  
Cynomolgus Monkey ◽  
Dna Sequence Analysis

220 NONHUMAN PRIMATE EMBRYONIC STEM CELLS SIMILAR TO THE BIOLOGICAL PROPERTIES OF MOUSE EMBRYONIC STEM CELLS

2012 ◽  
Vol 24 (1) ◽  
pp. 222
Author(s):  
A. Kusanagi ◽  
J. Yamasaki ◽  
C. Iwatani ◽  
H. Tsuchiya ◽  
R. Torii
Keyword(s):  
Nonhuman Primate ◽  
Cynomolgus Monkey ◽  
Es Cells ◽  
Embryonic Stem ◽  
Biological Properties ◽  
Es Cell ◽  
Mouse Es Cells ◽  
Mouse Es Cell

Human and mouse embryonic stem (ES) cells are derived from the inner cell mass of preimplantation blastocysts and human ES cells were long thought to be equivalent to mouse ES cells, despite clear morphological difference and different signalling pathways to maintain their pluripotency between these two ES cell types. Mouse ES cells depend on leukemia inhibitory factor (LIF) and bone morphogenic protein 4 (BMP4) signalling, whereas their human counterparts rely on basic fibroblast growth factor (bFGF) and activin A signalling. The biggest difference of two ES cells is the ability of chimera formation and mouse ES cells can contribute chimera but primate ES cells fails to do that. Monkey ES cells in primates only can be tested for chimera formation in vivo due to the ethical issue and cynomolgus monkey is the most common nonhuman primate to be used for the safety study of drug discoveries. The objective of this study was to develop novel cynomolgus monkey ES cells that have similar biological properties with mouse ES cell and our ultimate goal is to establish germline competent nonhuman primate ES cells. Ovarian stimulation and oocyte collection were carried out for the derivation of ES cells as previously described by Torii et al. Briefly, GnRH (0.9 mg/head) was administered to cynomolgus monkey and two weeks later, a micro infusion pump (iPRECIO™, Primetech Corp) contains FSH was implanted subcutaneously. Follicular aspiration was then performed 40 h after hCG injection and metaphase II oocytes were fertilized by intracytoplasmic sperm injection (ICSI). Cynomolgus monkey ES cells were then established under mouse ES cell conditions such as LIF/STAT signalling and a dome tree-dimensional (3D) morphology nonhuman primate ES cells were selected. On the other hands, ES cells that were established with the presence of basic FGF showed conventional layer-type morphology. Dome-type ES cells express pluripotent transcriptional factors such as Oct-3/4, Nonog and Sox2 as same as layer-type ES cells and both ES lines were capable of multilineage differentiations in vitro after embryoid body formation. Dome-type nonhuman ES cells can also form teratomas and differentiated into all three germ layers when grafted into immunodeficiency mice. For fluorescent gene delivery to nonhuman primate ES cells, feeder-free condition was applied and CAG-GFP vector was transfected into ES cells using Neon electroporation system (Invitrogen Inc.) for the tracing ES cells in the transplantation study. In this study, we have established dome-type ES cell lines that similar to mouse ES cells in morphology and signalling pathway. Dome-type nonhuman primate ES cells express pluripotent gene markers and prove their pluripotency both of in vitro and in vivo, in addition, these modifications would be important to create germline competent ES cells.

In Vivo Depletion of Cynomolgus Monkey B Cells Targeted by a Novel Monoclonal Antibody (Xi-20H5) Specific for a Shared Portion of the Human Immunoglobulin Variable Light Chain Lambda 1.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2354-2354
Author(s):  
Thierry Sornasse ◽  
Keri Tate ◽  
Kimberly Milner ◽  
Thomas Theriault ◽  
Dan W. Denney ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
Peripheral Blood ◽  
Cynomolgus Monkey ◽  
Patient Specific ◽  
B Cell Malignancies ◽  
Variable Regions ◽  
Variable Light

Abstract Genitope is developing a novel, personalized treatment for surface immunoglobulin (Ig) positive B cell malignancies. This treatment is based on a panel of monoclonal antibodies (Mabs) directed against shared epitopes expressed on different subsets of the variable regions of human Ig. The concept of targeting surface tumor Ig was explored in a series of clinical trials performed by Dr. Ronald Levy and his colleagues at Stanford. In these studies, Mabs directed against patient specific (idiotypic) determinants of the surface tumor Ig produced significant clinical benefit in relapsed follicular non-Hodgkin’s lymphoma patients. A number of these patients have had long term remissions. In Genitope’s planned clinical use, each patient will receive a single Mab from the panel selected based on its reactivity with the patient’s tumor. The selected Mab will react with the patient’s tumor and a minority of normal B cells, leaving the majority of the normal B cell repertoire intact. The ability of the panel members to provide therapeutic effect requires binding to tumor surface Ig in the presence of serum containing soluble Ig molecules. Mab Xi-20H5, a member of this panel of antibodies, is specific for a shared determinant on the human Ig variable light chain lambda 1. It binds to 25 to 35% of normal human B cells from peripheral blood and to 20 to 30% of normal cynomolgus monkey B cells from peripheral blood. In this study, we sought to demonstrate that, despite the presence of serum Ig, Mab Xi-20H5 would bind to surface Ig expressed on monkey B cells in vivo, resulting in specific depletion of target B cells. Six naïve cynomolgus monkeys received 8 intravenous infusions of the Mab Xi-20H5 at a dose of 40 mg/kg on days 1, 2, 3, 4, 7, 10, 14 & 17. Two naïve control animals received 8 infusions of vehicle only following the same schedule. The frequencies of lymphocyte sub-populations and of target B cells were monitored by flow cytometry on plasma-depleted whole blood samples. Samples were collected 23 hours after each infusion. In addition, two baseline samples were collected prior to treatment. The frequencies of lymphocyte sub-populations and of target B cells were compared to the average of the two baseline measurements. Frequencies of target B cells bound by Mab Xi-20H5 decreased in all treated animals while no significant change was detectable in the control animals. The bulk of the reduction in target B cell frequencies was observed 23 hours after the first infusion (range: 22% – 62%, average 41%). Frequencies of target B cells continued to decrease moderately with additional daily infusions (days 2 – 4), resulting in maximum reduction in target B cell frequency at 23 h post infusion 4 (range: 39% – 78%, average 54%). The frequencies of total B and T lymphocytes did not significantly change during the treatment. In vivo administration of Mab Xi-20H5 results in depletion of target B cells in a manner consistent with the expectation of an immunotherapeutic Mab aimed at treating surface Ig expressing B cell malignancies.

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