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differences in frontal network anatomy across primate species.the frontal lobe is central to distinctive aspects of human cognition and behavior. some comparative studies link this to a larger frontal cortex and even larger frontal white matter in humans compared with other primates, yet others dispute these findings. the discrepancies between studies could be explained by limitations of the methods used to quantify volume differences across species, especially when applied to white matter connections. in this study, we used a novel tractography approach t ...202031949106
interleukin-1β and tumor necrosis factor-α affect cytochrome p450 expression in cynomolgus macaque hepatocytes.the cynomolgus macaque, partly due to its evolutionary closeness to humans, is an important nonhuman primate species used in drug metabolism studies. in humans, expressions of cytochromes p450 (p450s), including the important drug-metabolizing enzyme p450 3a4, are affected by various cytokines. however, this phenomenon has not been fully investigated in cynomolgus macaques. in this study, the effects of cytokines on p450 expression were investigated using the quantitative polymerase chain reacti ...202032253084
generation of transgenic cynomolgus monkeys overexpressing the gene for amyloid-β precursor protein.alzheimer's disease (ad) is the most common cause of dementia and understanding its pathogenesis should lead to improved therapeutic and diagnostic methods. although several groups have developed transgenic mouse models overexpressing the human amyloid-β precursor protein (app) gene with ad mutations, with and without presenilin mutations, as well as app gene knock-in mouse models, these animals display amyloid pathology but do not show neurofibrillary tangles or neuronal loss. this presumably i ...202032250299
group size experiences with enhanced pre- and postnatal development studies in the long-tailed macaque (macaca fascicularis).enhanced pre- and postnatal development (eppnd) studies have become the default developmental toxicity test for biopharmaceuticals if nonhuman primates represent the relevant species. spontaneous pregnancy losses and infant deaths can be significant in macaques such as long-tailed macaques. the international council for harmonisation of technical requirements for pharmaceuticals for human use (ich) guideline s6(r1) states that pregnancy outcome can be judged also by the normogram-based variabili ...202032232119
excretion of the polymyxin derivative nab739 in murine urine.extremely multiresistant strains of enterobacteriaceae are emerging and spreading at a worrisome pace. polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. we have previously shown that novel polymyxin derivatives nab739 and nab815 are less nephrotoxic in cynomolgus monkeys than polymyxin b and are therapeutic in murine escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin b. here we evaluated whether the increased ...202032230751
biophysical and immunological characterization and in vivo pharmacokinetics and toxicology in nonhuman primates of the anti-pd-1 antibody pembrolizumab.the programmed cell death 1 (pd-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active t-cell immune surveillance. pembrolizumab (keytruda®, mk-3475) is a potent and highly selective humanized mab of the igg4/kappa isotype designed to directly block the interaction between pd-1 and its ligands, pd-l1 and pd-l2. this blockade enhances the functional activity of t cells to facilitate tumor regression and ultimately immune rej ...202032229606
prolonged intraocular residence and retinal tissue distribution of a fourth-generation compstatin-based c3 inhibitor in non-human primates.age-related macular degeneration (amd) is a leading cause of irreversible vision loss among the elderly population. genetic studies in susceptible individuals have linked this ocular disease to deregulated complement activity that culminates in increased c3 turnover, retinal inflammation and photoreceptor loss. therapeutic targeting of c3 has therefore emerged as a promising strategy for broadly intercepting the detrimental proinflammatory consequences of complement activation in the retinal tis ...202032229292
toward development of the delayed tolerance induction protocol for vascularized composite allografts in nonhuman primates.transplantation of vascularized composite allografts is limited mainly by the need for life-long immunosuppression. the consequent side effects and looming specter of chronic rejection portend eventual allograft loss. development of tolerogenic protocols is thus of utmost importance to the field of vascularized composite allograft transplantation.202032221215
rhesus macaques are most likely the ancestral source of helicobacter suis infection in pigs and not cynomolgus macaques. 202032219893
innate and secondary humoral responses are improved by increasing the time between mva vaccine immunizations.comprehending the mechanisms behind the impact of vaccine regimens on immunity is critical for improving vaccines. indeed, the time-interval between immunizations may influence b and t cells, as well as innate responses. we compared two vaccine schedules using cynomolgus macaques immunized with an attenuated vaccinia virus. two subcutaneous injections 2 weeks apart led to an impaired secondary antibody response and similar innate myeloid responses to both immunizations. in contrast, a delayed bo ...202032218996
development and validation of a multiplex immunoassay for the simultaneous quantification of type-specific igg antibodies to e6/e7 oncoproteins of hpv16 and hpv18.more than 170 types of human papilloma viruses (hpv) exist with many causing proliferative diseases linked to malignancy in indications such as cervical cancer and head and neck squamous cell carcinoma. characterization of antibody levels toward hpv serology is challenging due to complex biology of oncoproteins, pre-existing titers to multiple hpv types, cross-reactivity, and low affinity, polyclonal responses. using multiplex technology from msd, we have developed an assay that simultaneously c ...202032214362
early transcriptional changes within liver, adrenal gland, and lymphoid tissues significantly contribute to ebola virus pathogenesis in cynomolgus macaques.ebola virus (ebov) continues to pose a significant threat to human health, as evidenced by the 2013-2016 epidemic in west africa and the ongoing outbreak in the democratic republic of the congo. ebov causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. this high lethality combined with the paucity of licensed medical countermeasures makes ebov a critical human pathogen. although ebov infection results in significant damage to the liver ...202032213610
an optimized purified inactivated zika vaccine provides sustained immunogenicity and protection in cynomolgus macaques.the recent spread of zika virus (zikv) through the americas and caribbean and its devastating consequences for pregnant women and their babies have driven the search for a safe and efficacious zikv vaccine. among the vaccine candidates, a first-generation zikv purified inactivated vaccine (zpiv), adjuvanted with aluminum hydroxide, developed by the walter reed army institute of research (wrair), has elicited high seroconversion rates in participants in three phase-i clinical trials. in collabora ...202032194996
a pathology review of the lower gastrointestinal tract in relation to ulcerative colitis in rats and cynomolgus macaques treated with ammonium perfluorooctanoate.among many short-term, subchronic, and chronic toxicology studies with ammonium perfluorooctanoate (pfoa), the gastrointestinal tract has not been identified as a target organ for pfoa-related toxicity in laboratory animals where the corresponding serum pfoa concentrations typically approach several orders of magnitude higher than the general human population. these lack of gastrointestinal tract-related findings were in direct contrast to an epidemiological observation where a positive trend wa ...202032186254
association of antimicrobial resistance and gut microbiota composition in human and non-human primates at an urban ecotourism site.the rise of nature-based ecotourism in the past decade has introduced unprecedented challenges in managing the increasing interaction between humans and animals. the potential transmission of antibiotic resistant microbes between humans and non-human primate populations is a concern due to their genetic similarity. malaysia is well known for hotspots of wildlife diversity where non-human primates like monkeys and orangutans have become popular tourist attractions. in this study, we assessed the ...202032175011
a cervical spinal cord hemi-contusion injury model based on displacement control in non-human primates (macaca fascicularis).non-human primate (nhp) spinal cord injury (sci) models can be informative in the evaluation of treatments that show promise in rodent models prior to translation to humans. in the present study, we aimed to establish a cervical spinal hemi-contusion model with controlled displacement and evaluate the abnormalities in behavior, electrophysiology, histology, and magnetic resonance imaging. twelve adult nhps were divided into an sci group (n = 8, 24 and 48 weeks) and a control group (n = 4). an im ...202032174266
echocardiographic evaluation of cardiac function in cynomolgus monkeys over a wide age range.various cardiovascular diseases can be detected and diagnosed using echocardiography. the demand for cardiovascular system research using nonhuman primates is increasing, but echocardiographic references for nonhuman primates are limited. this report describes the first comparison of echocardiographic reference values in 247 normal cynomolgus monkeys (135 females, 112 males) over a wide age range. echocardiography, electrocardiography, blood pressure and chest x-ray images were acquired under im ...202032173671
synthesis, biodistribution, and radiation dosimetry of a novel mglur5 radioligand: 18f-azd9272.the metabotropic glutamate receptor subtype mglur5 has been proposed as a potential drug target for cns disorders such as anxiety, depression, parkinson's disease, and epilepsy. the astrazeneca compound azd9272 has previously been labeled with carbon-11 and used as a pet radioligand for mglur5 receptor binding. the molecular structure of azd9272 allows one to label the molecule with fluorine-18 without altering the structure. the aim of this study was to develop a fluorine-18 analogue of azd9272 ...202032167745
local field potentials for bci control.the gold standard in brain-computer interface (bci) modalities is multi single-unit recordings in the primary motor cortex. it yields the fastest and most elegant control (i.e., most degrees of freedom and bitrate). unfortunately, single-unit electrodes are prone to encapsulation, which limit their single-unit recording life. however, encapsulation does not significantly affect intracortical local field potentials (lfps). lfps and single-unit activity were recorded from the motor cortices of thr ...202032164859
retinal features in cynomolgus macaques (macaca fascicularis) assessed by using scanning laser ophthalmoscopy and spectral domain optical coherence tomography.cynomolgus macaques are an important and commonly used species in preclinical toxicology studies, but structural reports of in vivo retinal findings are rare in this species. the purpose of this study was to diminish this gap and document optical coherence tomography and scanning laser ophthalmoscopy imaging data in the healthy posterior pole of cynomolgus monkeys' eyes at predose examinations. the current study is a retrospective assessment of baseline spectral domain oct data obtained from the ...202032164796
pharmacokinetics of polyethylene glycol-modified canine uricase following single and multiple intravenous injections in cynomolgus monkeys.polyethylene glycol-modified canine uricase (peg-uhc) prepared with a lower-molecular-weight (5 kda) peg is used to treat gout. this study investigated the comparative pharmacokinetics of single and multiple doses of peg-uhc administered intravenously and a single dose of uricase (uhc) administered intravenously in cynomolgus monkeys.202032162270
differentiated agonistic antibody targeting cd137 eradicates large tumors without hepatotoxicity.cd137 (4-1bb) is a member of the tnfr superfamily that represents a promising target for cancer immunotherapy. recent insights into the function of tnfr agonist antibodies implicate epitope, affinity, and igg subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested cd137 agonists. here, we describe the preclinical characterization of ctx-471, a fully human igg4 agonist of cd137 that engages a unique epitope that is shared by ...202032161196
simplified drug efficacy screening system for sleep-disorder drugs using non-human primates.the most widely used animal models to develop sleep-disorder drugs are rodents, particularly rats and mice. however, unlike humans, these rodents are nocturnal. thus, diurnal non-human primates represent a valuable and more translational animal model to study sleep. although sleep-disorder drugs have been screened in non-human primates, the use of a telemetry system is not a desirable method for a rapid drug efficacy assessment system because of the need for expensive equipment, complicated surg ...202032154428
a novel c2 domain binding cd33xcd3 bispecific antibody with potent t-cell redirection activity against acute myeloid leukemia.cd33 is expressed in 90% of patients with acute myeloid leukemia (aml), and its extracellular portion consists of a v domain and a c2 domain. a recent study showed that a single nucleotide polymorphism (snp), rs12459419 (c > t), results in the reduced expression of v domain-containing cd33 and limited efficacy of v domain-binding anti-cd33 antibodies. we developed jnj-67571244, a novel human bispecific antibody capable of binding to the c2 domain of cd33 and to cd3, to induce t-cell recruitment ...202032150609
preclinical testing of aav9-php.b for transgene expression in the non-human primate cochlea.in a number of mouse models of hereditary deafness, therapeutic transgene delivery to the cochlea and vestibular organs using adeno-associated viral vectors (aavs) has shown striking rescue of hearing and balance. however, only a subset of aav capsids have shown efficacy in transducing both inner hair cells and outer hair cells, and it is also not clear which of these can be translated to treatment of human inner ear. we recently reported efficient transgene expression of a gfp reporter in a non ...202032145977
ribavirin does not potentiate favipiravir antiviral activity against ebola virus in non-human primates.in spite of recurrent and dramatic outbreaks, there are no therapeutics approved against ebola virus disease. favipiravir, a rna polymerase inhibitor active against several rna viruses, recently demonstrated significant but not complete protection in a non-human primate model of ebola virus disease. in this study, we assessed the benefit of the combination of favipiravir and ribavirin, another broad spectrum antiviral agent, in the same model.202032135218
autologous fibroblasts induce fibrosis of the nucleus pulposus to maintain the stability of degenerative intervertebral discs.lumbar degenerative disc diseases cause low back pain (lbp). the maintenance of the height and stability of the intervertebral disc (ivd) space is an effective treatment for lbp. the following study evaluated the effects of fibroblast injection on intervertebral disc degeneration (idd) in a preclinical setting. compared with the idd group, the fibroblast treatment group demonstrated effective maintenance of ivd height, reduced endplate degeneration, and improved nuclear magnetic resonance signal ...202032128275
cynomolgus monkeys with spontaneous type-2-diabetes-mellitus-like pathology develop alpha-synuclein alterations reminiscent of prodromal parkinson's disease and related diseases.available evidence suggests that diabetes mellitus (dm) is a non-genetic risk factor for parkinson's disease (pd). pd and dm have shared similarities in pathogenetic mechanisms, including age, environmental factors, inflammatory reaction, and protein aggregation, etc. α-synuclein is the primary protein component in the protein inclusions in pd, while islet amyloid polypeptide (iapp) aggregates to form amyloid structures in β cells in type 2 diabetes mellitus (t2dm). pancreatic and cerebral funct ...202032116510
characterization of 100 extended major histocompatibility complex haplotypes in indonesian cynomolgus macaques.many medical advancements-including improvements to anti-rejection therapies in transplantation and vaccine development-rely on preclinical studies conducted in cynomolgus macaques (macaca fascicularis). major histocompatibility complex (mhc) class i and class ii genes of cynomolgus macaques are orthologous to human leukocyte antigen complex (hla) class i and class ii genes, respectively. both encode cell-surface proteins involved in cell recognition and rejection of non-host tissues. mhc class ...202032112172
unparalleled rapid evolution of kir genes in rhesus and cynomolgus macaque populations.the killer cell ig-like receptors (kir) modulate immune responses through interactions with mhc class i molecules. the kir region in large cohorts of rhesus and cynomolgus macaque populations were characterized, and the experimental design enabled the definition of a considerable number of alleles (n = 576) and haplotypes, which are highly variable with regard to architecture. although high levels of polymorphism were recorded, only a few alleles are shared between species and populations. the r ...202032111732
identification and preclinical development of an anti-proteolytic upa antibody for rheumatoid arthritis.blocking the proteolytic capacity of urokinase-type plasminogen activator (upa) with a monoclonal antibody (mab) reduces arthritis progression in the collagen-induced mouse arthritis model to an extent that is on par with the effect of blocking tumor necrosis factor-alpha by etanercept. seeking to develop a novel therapy for rheumatoid arthritis, a humanized mab, nnc0266-0043, was selected for its dual inhibition of both the zymogen activation and the proteolytic capacity of human upa. the antib ...202032108909
does rank rule? rank-related grooming patterns in nicobar long-tailed macaques macaca fascicularis umbrosus.primates maintain social bonds with specific individuals in the group by directing grooming toward them. social grooming is often targeted toward individuals with whom the most benefits can be exchanged, which are usually the high-ranking individuals. we used the seyfarth model to investigate whether dominance rank alters the distribution of grooming in a group of macaca fascicularis umbrosus at great nicobar island. we investigated whether dominance rank predicted grooming rate in both males an ...202032108904
unusual sequence characteristics of human chromosome 19 are conserved across 11 nonhuman primates.human chromosome 19 has many unique characteristics including gene density more than double the genome-wide average and 20 large tandemly clustered gene families. it also has the highest gc content of any chromosome, especially outside gene clusters. the high gc content and concomitant high content of hypermutable cpg sites raises the possibility chromosome 19 exhibits higher levels of nucleotide diversity both within and between species, and may possess greater variation in dna methylation that ...202032106815
hx008: a humanized pd-1 blocking antibody with potent antitumor activity and superior pharmacologic properties.through reactivating tumor-infiltrating lymphocytes, therapeutics targeting programmed cell death protein 1 (pd-1) demonstrate impressive clinical efficacy in the treatment of multiple cancers. in this report, we characterize hx008, a humanized igg4s228p anti-pd-1 monoclonal antibody with an engineered fc domain, in a series of in vitro assays and in vivo studies. in vitro, hx008 binds to human pd-1 with high affinity and potently suppresses the interaction of pd-1 with pd-l1 and pd-l2. the lack ...202032106752
summary of a workshop on preclinical and translational safety assessment of cd3 bispecifics.currently, there is a multitude of cd3 bispecifics with different molecular designs and binding properties in preclinical and clinical development for the treatment of liquid or solid tumors. the key safety concerns with cd3 bispecifics are excessive release of cytokines, which may translate to potentially life-threating cytokine release syndrome (crs), target organ toxicity due to redirection of t-cells to normal tissues expressing the tumor-associated antigen (taa) (off-tumor/on-target cytotox ...202032100588
leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis.tuberculosis (tb) caused by mycobacterium tuberculosis (mtb) is a global health problem. at present, prior exposure to mtb can be determined by blood-based interferon-gamma release assay (igra), but active tb is not always detectable by blood tests such as crp and esr. this study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (lrg), a new inflammatory biomarker, could be used to assess active disease of tb. cynomolgus macaques pretreated with or without bacille calmette- ...202032099022
habitat suitability analysis reveals high ecological flexibility in a "strict" forest primate.research of many mammal species tends to focus on single habitats, reducing knowledge of ecological flexibility. the javan lutung (trachypithecus auratus) is considered a strict forest primate, and little is known about populations living in savannah. in 2017-2018, we investigated the density and distribution of javan lutung in baluran national park, indonesia. we conducted ad libitum follows and line transect distance sampling with habitat suitability analysis of javan lutung.202032095154
an akr1c3-specific prodrug with potent anti-tumor activities against t-all.akr1c3 overexpression has been reported in various types of cancers, including t-all. ast-006 (th-3424), an akr1c3-specific prodrug, was reported recently to have potent cytotoxicity against liver cancer cells overexpressing akr1c3 and t-all. in this study, ast-006 demonstrated potent anti-tumor activity against different t-all cell lines in vitro and in vivo, including patient-derived xenograft (pdx) model. ast-006 also exhibited minimal cytotoxicity against primary human t-cells in vitro and l ...202032091283
venezuelan equine encephalitis vaccine with rearranged genome resists reversion and protects non-human primates from viremia after aerosol challenge.live-attenuated v4020 vaccine for venezuelan equine encephalitis virus (veev) containing attenuating rearrangement of the virus structural genes was evaluated in a non-human primate model for immunogenicity and protective efficacy against aerosol challenge with wild-type veev. the genomic rna of v4020 vaccine virus was encoded in the pmg4020 plasmid under control of the cmv promoter and contained the capsid gene downstream from the glycoprotein genes. it also included attenuating mutations from ...202032085953
proteome array of antibody responses to chlamydia trachomatis infection in nonhuman primates.nonhuman primates have been used to investigate pathogenic mechanisms and evaluate immune responses following chlamydia trachomatis inoculation. this study aimed to systemically profile antibody responses to c. trachomatis infection in nonhuman primates.202032084433
validation of a de-immunization strategy for monoclonal antibodies using cynomolgus macaque as a surrogate for human.the immunogenicity of biotherapeutics presents a major challenge during the clinical development of new protein drugs including monoclonal antibodies. to address this, multiple humanization and de-immunization techniques that employ in silico algorithms and in vitro test systems have been proposed and implemented. however, the success of these approaches has been variable and to date, the ability of these techniques to predict immunogenicity has not been systematically tested in humans or other ...202032080869
thalamic afferents emphasize the different functions of macaque precuneate areas.we studied the thalamic afferents to cortical areas in the precuneus using injections of retrograde fluorescent neuronal tracers in four male macaques (macaca fascicularis). six injections were within the limits of cytoarchitectural area pgm, one in area 31 and one in area peci. precuneate areas shared strong input from the posterior thalamus (lateral posterior nucleus and pulvinar complex) and moderate input from the medial, lateral, and intralaminar thalamic regions. area pgm received strong c ...202032078035
a potent pan-tgfβ neutralizing monoclonal antibody elicits cardiovascular toxicity in mice and cynomolgus monkeys.transforming growth factor β (tgfβ) signaling has been recently shown to reduce antitumor response to pd-l1 blockade, leading to a renewed enthusiasm in developing anti-tgfβ therapies for potential combination with cancer immunotherapy agents. inhibition of tgfβ signaling in nonclinical toxicology species is associated with serious adverse toxicities including cardiac valvulopathies and anemia. previously, cardiovascular toxicities have been thought to be limited to small molecule inhibitors of ...202032077954
cerebrospinal fluid characterization in cynomolgus monkeys, beagle dogs, and göttingen minipigs.intrathecal administration is an important route for drug delivery, and in pharmacology and toxicology studies, cerebrospinal fluid (csf) collection and analysis is required for evaluating blood-brain barrier penetration and central nervous system exposure. the characteristics of csf in commonly used nonrodent models are lacking. the purpose of this study is to evaluate and provide some insights into normal cellular and biochemical composition of csf as well as diffusion potential following intr ...202032066300
novel abs targeting the n-terminus of fibroblast growth factor 19 inhibit hepatocellular carcinoma growth without bile-acid-related side-effects.hepatocellular carcinoma (hcc) is a common and particularly fatal form of cancer for which very few drugs are effective. the fibroblast growth factor 19 (fgf19) has been viewed as a driver of hcc development and a potential ab target for developing novel hcc therapy. however, a previously developed anti-fgf19 ab disrupted fgf19's normal regulatory function and caused severe bile-acid-related side-effects despite of having potent antitumor effects in preclinical models. here, we developed novel h ...202032061104
novel liver fibrosis model in macaca fascicularis induced by thioacetamide.although transplantation is the only definitive treatment for liver cirrhosis, there remains a shortage of donors, necessitating that novel treatments be developed. we aimed to establish a liver fibrosis model in macaca fascicularis that can help accelerate preclinical research. liver fibrosis was induced by administering thioacetamide (taa) and carbon tetrachloride (ccl4). analysis of residual liver function and fibrosis progression was based on clinical indices, such as the child-pugh score or ...202032051422
functional clusters of neurons in layer 6 of macaque v1.layer 6 appears to perform a very important role in the function of macaque primary visual cortex, v1, but not enough is understood about the functional characteristics of neurons in the layer 6 population. it is unclear to what extent the population is homogeneous with respect to their visual properties or if one can identify distinct subpopulations. here we performed a cluster analysis based on measurements of the responses of single neurons in layer 6 of primary visual cortex in male macaque ...202032041896
a selective androgen receptor modulator sarm-2f activates androgen receptor, increases lean body mass, and suppresses blood lipid levels in cynomolgus monkeys.sarm-2f a selective androgen receptor (ar) modulator, increases skeletal muscle mass and locomotor activity in rats. this study aimed to clarify its pharmacological effects in monkeys. in reporter assays, the ec50 values of sarm-2f for rat, monkey, and human ar were 2.5, 3, and 3.6 nmol/l, respectively; those of testosterone were 12, 3.2, and 11 nmol/l, respectively. a single oral administration (10 mg/kg sarm-2f) produced a maximal plasma concentration of 3011 ng/ml, with an area under the 24 h ...202032030892
4-week toxicity study of biosimilar natalizumab in comparison to tysabri® by repeated intravenous infusion to cynomolgus monkeys.the objective of the study was to obtain information on the toxicity of biosimilar natalizumab (pb006) in comparison to the reference product tysabri®. cynomolgus monkeys (15 males and 15 females), three animals per sex and group were treated with either pb006 or the reference product tysabri® at dose levels of 3 or 30 mg/kg body weight or placebo by intravenous infusion every other day for a period of 4 weeks. the study is also meant to facilitate ethics committee approval in specific countries ...202032024395
do males bond? a study of male-male relationships in nicobar long-tailed macaques macaca fascicularis umbrosus.in primates, males compete for a mate, which is a non-sharable resource. this makes the conditions less conducive for males to have stable relationships. one such special kind of relationship is a bond where the interactions are reciprocated, equitable and differentiated. bonds in macaque societies are based on the degree of within-group contest competition for mates which is dependent on the synchronization of female fertile phase and reliability of fertility signals. species of the fasciculari ...202032020904
kmrc011, an agonist of toll-like receptor 5, mitigates irradiation-induced tissue damage and mortality in cynomolgus monkeys.in the study here, the potential applicability of kmrc011 - an agonist of toll-like receptor-5 - as a countermeasure for radiation toxicities was evaluated. following a single 5.5 gy total body irradiation (tbi, surface absorbed dose = 7 gy) of co60 γ-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received tbi only and a group that was injected once with kmrc011 (10 μg/kg) after tbi. compared to the tbi-only hosts (80%), the de ...202032013650
the development and characterization of a long acting anti-thrombotic von willebrand factor (vwf) aptamer.thrombus formation involves coagulation proteins and platelets. the latter, referred to as platelet-mediated thrombogenesis, is predominant in arterial circulation. platelet thrombogenesis follows vascular injury when extracellular von willebrand factor (vwf) binds via its a3 domain to exposed collagen, and the free vwf a1 domain binds to platelet glycoprotein ib (gpib).202032011054
atypical presentation and pathogenesis of a macaque lymphocryptoviral-associated b-cell lymphoma in a cynomolgus monkey.we report the unique pathogenesis and presentation of a rapidly progressive b-cell lymphoma in a 3-year-old female cynomolgus monkey on day 50 of a 13-week toxicity study. clinical pathology evaluation revealed a marked leukocytosis with bicytopenia. a serum protein electrophoresis was consistent with monoclonal gammopathy. the architecture of the lymph node, spleen, and thymus were variably effaced by neoplastic cells, which also infiltrated other tissues. immunohistochemistry of the affected t ...202032009251
comparative nonclinical assessments of the biosimilar pf-06410293 and originator adalimumab.adalimumab, a recombinant fully human monoclonal antibody targeting tumor necrosis factor (tnf), is approved in the united states and europe to treat various inflammatory and autoimmune indications. biosimilars are approved biologics highly similar, but not identical, to approved biotherapeutics. to support clinical development of pf-06410293, an adalimumab biosimilar, nonclinical studies evaluated the structural, functional, toxicologic, and toxicokinetic similarity to originator adalimumab sou ...202032006671
fluoroquinolones suppress gluconeogenesis by inhibiting fructose 1,6-bisphosphatase in primary monkey hepatocytes.dysglycemia is one of the most serious adverse events associated with the clinical use of certain fluoroquinolones. the purpose of this study was to investigate the effects of the representative fluoroquinolones moxifloxacin and gatifloxacin on hepatic gluconeogenesis using primary monkey hepatocytes. glucose production was induced after the cells were incubated for 4 h with 10 mm sodium lactate and 1 mm sodium pyruvate as gluconeogenic substrates. under these conditions, moxifloxacin and gatifl ...202032004540
improved translation of stability for conjugated antibodies using an in vitro whole blood assay.for antibody-drug conjugates to be efficacious and safe, they must be stable in circulation to carry the payload to the site of the targeted cell. several components of a drug-conjugated antibody are known to influence stability: 1) the site of drug attachment on the antibody, 2) the linker used to attach the payload to the antibody, and 3) the payload itself. in order to support the design and optimization of a high volume of drug conjugates and avoid unstable conjugates prior to testing in ani ...202031997712
a novel gucy2c-cd3 t-cell engaging bispecific construct (pf-07062119) for the treatment of gastrointestinal cancers.gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. here, we demonstrate potent, tumor-selective efficacy with pf-07062119, a t-cell engaging cd3 bispecific targeting tumors expressing guanylyl cyclase c (gucy2c), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. in addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis ...202031996389
changed pga and postn levels in choroid plexus are associated with depressive-like behaviors in mice.major depressive disorder (mdd) has become a potential cause of death and disability among young people worldwide. numerous studies have indicated that the different cerebrospinal fluid (csf) proteins may be used as mediums for mdd. given the emergent interest of csf proteins in mdd, we validated proteins expression in the choroid plexus (cp), the brain region that produces csf in the lateral ventricle, the third ventricle, and the fourth ventricle of the central nervous system (cns). the csf co ...202031983432
utilization of the chronic atrioventricular block cynomolgus monkey as an in vivo model to evaluate drug interaction-associated torsade de pointes.it has been difficult to experimentally reproduce synergistic effects of ketoconazole on terfenadine-induced torsade de pointes. we assessed proarrhythmic effects of terfenadine (30 mg/kg, p.o.) with/without ketoconazole (100 mg/kg, p.o.) pretreatment using the chronic atrioventricular block cynomolgus monkeys with repeated-measured design (n = 4). terfenadine with ketoconazole pretreatment repeatedly induced non-sustained torsade de pointes in each animal, although terfenadine alone did not ind ...202031982331
duobody-cd3xcd20 induces potent t-cell-mediated killing of malignant b cells in preclinical models and provides opportunities for subcutaneous dosing.duobody®-cd3xcd20 (gen3013) is a full-length human igg1 bispecific antibody (bsab) recognizing cd3 and cd20, generated by controlled fab-arm exchange. its fc domain was silenced by introduction of mutations l234f l235e d265a.202031981978
an optimized full-length flt3/cd3 bispecific antibody demonstrates potent anti-leukemia activity and reversible hematological toxicity.flt3 (fms-like tyrosine kinase 3), expressed on the surface of acute myeloid leukemia (aml) blasts, is a promising aml target, given its role in the development and progression of leukemia, and its limited expression in tissues outside the hematopoietic system. small molecule flt3 kinase inhibitors have been developed, but despite having clinical efficacy, they are effective only on a subset of patients and associated with high risk of relapse. a durable therapy that can target a wider populatio ...202031981494
comparative pharmacokinetics and pharmacodynamics of the advanced retinol-binding protein 4 antagonist in dog and cynomolgus monkey.accumulation of lipofuscin bisretinoids in the retina contributes to pathogenesis of macular degeneration. retinol-binding protein 4 (rbp4) antagonists reduce serum retinol concentrations thus partially reducing retinol delivery to the retina which decreases bisretinoid synthesis. bpn-14136 is a novel rbp4 antagonist with good in vitro potency and selectivity and optimal rodent pharmacokinetic (pk) and pharmacodynamic (pd) characteristics. to select a non-rodent species for regulatory toxicology ...202031978148
quantification of regional myocardial mean intracellular water lifetime: a nonhuman primate study in myocardial stress.heart failure with preserved ejection fraction (hfpef) is typically associated with early metabolic remodeling. noninvasive imaging biomarkers that reflect these changes will be crucial in determining responses to early drug interventions in these patients. mean intracellular water lifetime (τi ) has been shown to be partially inversely related to na, k-atpase transporter activity and may thus provide insight into the metabolic status in hfpef patients. here, we aim to perform regional quantific ...202031977123
epitope and fc-mediated cross-linking, but not high affinity, are critical for antitumor activity of cd137 agonist antibody with reduced liver toxicity.cd137 (tnfrsf9, 4-1bb) agonist antibodies (mab) have demonstrated potent antitumor activity with memory response while causing hepatotoxicity in mouse models. in clinical trials, the degrees of liver toxicity of anti-cd137 vary from grade 4 transaminitis (urelumab) to nonexistent (utomilumab). to exploit the antitumor potential of cd137 signaling, we identified a new class of cd137 agonist mabs with strong antitumor potency without significant transaminitis in vivo compared with cd137 agonists p ...202031974274
integrated whole liver histologic analysis of the allogeneic islet distribution and characteristics in a nonhuman primate model.the most obvious method to observe transplanted islets in the liver is direct biopsy, but the distribution and location of the best biopsy site in the recipient's liver are poorly understood. islets transplanted into the whole liver of five diabetic cynomolgus monkeys that underwent insulin-independent survival for an extended period of time after allo-islet transplantation were analyzed for characteristics and distribution tendency. the liver was divided into segments (s1-s8), and immunohistoch ...202031964980
mrna levels of drug-metabolizing enzymes in 11 brain regions of cynomolgus macaques.the cynomolgus macaque is an important nonhuman primate species in drug metabolism studies, in part because of its evolutionary closeness to humans. cytochromes p450 (p450s) have been investigated in the major drug-metabolizing organs, i.e., the liver and small intestine, but have not been fully investigated in the brain. however, recent investigations have indicated possible important roles for p450s in the brain. in this study, by using the quantitative polymerase chain reaction, we measured t ...202031964621
characterization of a renal hypertensive model in telemetrized cynomolgus monkeys. 202031963043
dual effect of clonidine on qt interval duration and body temperature in cynomolgus monkeys: qt correction formula for changes in core body temperature. 202031962962
validation of gluteus medius muscle electromyographic (emg) recording by telemetry in socialized cynomolgus monkeys. 202031962961
assessment of relative sensitivities of crossover and ascending-dose study designs for cardiovascular telemetry evaluation in cynomolgus monkeys. 202031962956
comparison of different qtc formulae for correction of qt interval in cynomolgus monkeys. 202031962954
age-related effects of heroin on gene expression in the hippocampus and striatum of cynomolgus monkeys.the aim of this study was to investigate differentially expressed genes and their functions in the hippocampus and striatum after heroin administration in cynomolgus macaques of different ages.202031958910
in vitro characterization of the thermoneutral transient receptor potential vanilloid-1 (trpv1) inhibitor grte16523.the trpv1 ion channel is a neuronal sensor that plays an important role in nociception and neuropathic as well as inflammatory pain. in clinical trials, hyperthermia and thermo-hypoaesthesia turned out as major side effects of trpv1 antagonists, preventing successful development of such molecules as analgesics. in vitro studies demonstrated that the trpv1 ion channel is a polymodal sensor integrating stimuli from molecular modulators with temperature, ph and transmembrane potential. temperature ...202031954706
selection of preclinical models to evaluate intranasal brain cooling for acute ischemic stroke.stroke accounts for a large proportion of global mortality and morbidity. selective hypothermia, via intranasal cooling devices, is a promising intervention in acute ischemic stroke. however, prior to large clinical trials, preclinical studies in large animal models of ischemic stroke are needed to assess the efficacy, safety, and feasibility of intranasal cooling for selective hypothermia as a neuroprotective strategy. here, we review the available scientific literature for evidence supporting ...202031950091
vital, porcine, gal-knockout skin transplants provide efficacious temporary closure of full-thickness wounds: good laboratory practice-compliant studies in nonhuman primates.vital, genetically engineered porcine skin transplants have long been regarded as a promising treatment option for severe burn wounds. the objective of this two-part, preclinical study was to evaluate the ability of vital, split-thickness skin xenotransplants derived from designated pathogen-free, alpha 1,3 galactosyltransferase knockout miniature swine to provide temporary wound closure of full-thickness wound defects intended to model severe and extensive, deep partial- and full-thickness burn ...202031943027
exploratory clinical characterization of experimentally-induced ulcerative colitis nonhuman primates.a limitation of currently used preclinical models of colitis is that disease and treatment assessment methods differ from clinically used methods. thus, a modified mayo score and an endoscopic index (ei) were developed for use in cynomolgus macaques with 0.25% dextran sulfate sodium (dss)-induced ulcerative colitis. macaques were treated with water with dss for two weeks followed by water without dss for two weeks. disease activity was classified according to a modified mayo score: stool consist ...202031938753
preclinical development of a novel cd47 nanobody with less toxicity and enhanced anti-cancer therapeutic potential.cd47, the integrin-related protein, plays an important role in immune resistance and escape of tumor cells. antibodies blocking the cd47/sirpα signal pathway can effectively stimulate macrophage-mediated phagocytosis of tumor cells, which becomes a promising approach for tumor immunotherapy. nanobodies (nbs) derived from camelid animals are emerging as a new force in antibody therapy.202031931812
viral opportunistic infections in mauritian cynomolgus macaques undergoing allogeneic stem cell transplantation mirror human transplant infectious disease complications.allogeneic hematopoietic stem cell transplantation (hsct) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. here, in a mauritian cynomolgus macaque model of fully mhc-matched allogeneic hsct, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to hsct-associated human counterparts bk virus, epstein-barr virus, and human cytomegalovirus. viral replica ...202031930750
non-invasive molecular tracking method that measures ocular drug distribution in non-human primates.intravitreal (ivt) injection has become the standard route for drug administration in retinal diseases. however, the ability to measure biodistribution of ocular therapeutics in large species remains limited, due to the invasive nature of some techniques or their lack of spatial information. the aim of this study was to develop in cynomolgus monkeys a non-invasive fluorescence imaging technology that enables tracking of ivt-dosed drugs and could be easily translated into humans. here, we show a ...202031925329
malaria parasites in macaques in thailand: stump-tailed macaques (macaca arctoides) are new natural hosts for plasmodium knowlesi, plasmodium inui, plasmodium coatneyi and plasmodium fieldi.certain species of macaques are natural hosts of plasmodium knowlesi and plasmodium cynomolgi, which can both cause malaria in humans, and plasmodium inui, which can be experimentally transmitted to humans. a significant number of zoonotic malaria cases have been reported in humans throughout southeast asia, including thailand. there have been only two studies undertaken in thailand to identify malaria parasites in non-human primates in 6 provinces. the objective of this study was to determine t ...202033004070
seroprevalence of dengue, zika, and chikungunya viruses in wild monkeys in thailand.zoonotic pathogens such as arboviruses have comprised a significant proportion of emerging infectious diseases in humans. the role of wildlife species as reservoirs for arboviruses is poorly understood, especially in endemic areas such as southeast asia. this study aims to determine the exposure history of different macaque species from national parks in thailand to mosquito-borne flaviviruses and alphavirus by testing the serum samples collected from 25 northern pigtailed macaques, 33 stump-tai ...202032588813
aavrh10 vector corrects disease pathology in mps iiia mice and achieves widespread distribution of sgsh in large animal brains.patients with mucopolysaccharidosis type iiia (mps iiia) lack the lysosomal enzyme sulfamidase (sgsh), which is responsible for the degradation of heparan sulfate (hs). build-up of undegraded hs results in severe progressive neurodegeneration for which there is currently no treatment. the ability of the vector adeno-associated virus (aav)rh.10-cag-sgsh (lys-saf302) to correct disease pathology was evaluated in a mouse model for mps iiia. lys-saf302 was administered to 5-week-old mps iiia mice at ...202031909089
a lag-3-specific agonist antibody for the treatment of t cell-induced autoimmune diseases.t cells chronically stimulated with the same peptide tend to express exhaustion markers such as pd-1 or lag-3. deficiencies in the pd-1 and lag-3 pathways have been linked to the development of autoimmune diseases. imp761 is a lag-3-specific humanized agonist ab with immunosuppressive properties both in vitro and in vivo in an ag-specific delayed-type hypersensitivity (dth) model in the cynomolgus macaque (macaca fascicularis). imp761 inhibits tcr-mediated nfat activation and ag-induced human t ...202031907283
a novel lc-ms/ms approach to the pharmacokinetic study of free and bound aflibercept simultaneously.to comprehensively evaluate the pharmacokinetic (pk) characteristics of aflibercept, we established a liquid chromatography with tandem mass spectrometry (lc-ms/ms) method to determine the concentration of vascular endothelial growth factor (vegf)-a-bound aflibercept and free aflibercept. a specific sample preparation method of nano-surface and molecular-orientation limited (nsmol) proteolysis was performed to extract both free and bound aflibercept from plasma. the tryptic peptides unique to af ...202031897562
development of ao-176, a next-generation humanized anti-cd47 antibody with novel anticancer properties and negligible red blood cell binding.inhibitors of adaptive immune checkpoints have shown promise as cancer treatments. cd47 is an innate immune checkpoint receptor broadly expressed on normal tissues and overexpressed on many tumors. binding of tumor cd47 to signal regulatory protein alpha (sirpα) on macrophages and dendritic cells triggers a "don't eat me" signal that inhibits phagocytosis enabling escape of innate immune surveillance. blocking cd47/sirpα interaction promotes phagocytosis reducing tumor burden in numerous xenogra ...202031879362
chronic sub-anesthetic ketamine induces permanent hypolocomotion and impairment of hippocampus in adolescent cynomolgus monkeys.ketamine has gained increasing popularity in adolescent drug abusers worldwide. however, relatively little is known about the long-term effects of recreational ketamine on adolescent hippocampus. the present study investigates the effects of different periods (1, 3 and 6 months) of recreational ketamine administration on locomotor activity and neuron damage in the hippocampus of adolescent cynomolgus monkeys. 32 4-year-old male cynomolgus monkeys were divided into control, 1-month, 3-month and 6 ...202031863811
comments on 'in vitro culture of cynomolgus monkey embryos beyond early gastrulation'. 202031863115
il-10 impairs local immune response in lung granulomas and lymph nodes during early mycobacterium tuberculosis infection.tuberculosis (tb), caused by mycobacterium tuberculosis, continues to be a major global health problem. lung granulomas are organized structures of host immune cells that function to contain the bacteria. cytokine expression is a critical component of the protective immune response, but inappropriate cytokine expression can exacerbate tb. although the importance of proinflammatory cytokines in controlling m. tuberculosis infection has been established, the effects of anti-inflammatory cytokines, ...202031862711
cd40 enhances type i interferon responses downstream of cd47 blockade, bridging innate and adaptive immunity.disrupting the binding of cd47 to sirpα has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (adcp) of targeted antibodies. preclinically, cd47/sirpα blockade induces antitumor activity by increasing the phagocytosis of tumor cells by macrophages and enhancing the cross-presentation of tumor antigens to cd8+ t cells by dendritic cells; both of these processes are potentiated by cd40 signaling. here we generated a nove ...202031852716
neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys.hypobaric hypoxia (hh) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. previous studies on the mechanisms of hh-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. here, we report that cynomolgus monkeys ( macacafascicularis) exposed to acute hh developed human-like hh syndrome involving severe brain injury and abnormal be ...202031840949
chronic voluntary ethanol drinking in cynomolgus macaques elicits gene expression changes in prefrontal cortical area 46.genome-wide profiling to examine brain transcriptional features associated with excessive ethanol (etoh) consumption has been applied to a variety of species including rodents, nonhuman primates (nhps), and humans. however, these data were obtained from cross-sectional samples which are particularly vulnerable to individual variation when obtained from small outbred populations typical of human and nhp studies. in the current study, a novel within-subject design was used to examine the effects o ...202031840818
identification and characterization of a new carboxylesterase 2 isozyme, mfces2c, in the small intestine of cynomolgus monkeys.in contrast to a single human carboxylesterase 2 (ces2) isozyme (hce2), three ces2 genes have been identified in cynomolgus monkeys: mfces2a, mfces2b, and mfces2c. although mfces2a protein is expressed in several organs, mfces2b is a pseudogene and the phenotype of the mfces2c gene has not yet been clarified in tissues. in previous studies, we detected an unidentified esterase in the region of ces2 mobility upon nondenaturing page analysis of monkey intestinal microsomes, which showed immunoreac ...202031836607
quadrivalent vesiculovax vaccine protects nonhuman primates from viral-induced hemorrhagic fever and death.recent occurrences of filoviruses and the arenavirus lassa virus (lasv) in overlapping endemic areas of africa highlight the need for a prophylactic vaccine that would confer protection against all of these viruses that cause lethal hemorrhagic fever (hf). we developed a quadrivalent formulation of vesiculovax that contains recombinant vesicular stomatitis virus (rvsv) vectors expressing filovirus glycoproteins and that also contains a rvsv vector expressing the glycoprotein of a lineage iv stra ...202031820871
social influence on the expression of robbing and bartering behaviours in balinese long-tailed macaques.animals use social information, available from conspecifics, to learn and express novel and adaptive behaviours. amongst social learning mechanisms, response facilitation occurs when observing a demonstrator performing a behaviour temporarily increases the probability that the observer will perform the same behaviour shortly after. we studied "robbing and bartering" (rb), two behaviours routinely displayed by free-ranging long-tailed macaques (macaca fascicularis) at uluwatu temple, bali, indone ...202031820148
oral repeated-dose toxicity studies of bia 10-2474 in cynomolgus monkeys.bia 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1h-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (faah) inhibitor developed by bial for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (aea) such as pain disorders. during a phase i clinical trial one subject died after receiving bia 10-2474 and others displayed neurological signs. as part of series of papers presenting all the toxicology data available prior to the clin ...202031816339
poly-arginine peptide-18 (r18) reduces brain injury and improves functional outcomes in a nonhuman primate stroke model.poly-arginine peptide-18 (r18) is neuroprotective in different rodent middle cerebral artery occlusion (mcao) stroke models. in this study, we examined whether r18 treatment could reduce ischemic brain injury and improve functional outcome in a nonhuman primate (nhp) stroke model. a stroke was induced in male cynomolgus macaques by mcao distal to the orbitofrontal branch of the mca through a right pterional craniotomy, using a 5-mm titanium aneurysm clip for 90 min. r18 (1000 nmol/kg) or saline ...202031833045
domesticated cynomolgus monkey embryonic stem cells allow the generation of neonatal interspecies chimeric pigs.blastocyst complementation by pluripotent stem cell (psc) injection is believed to be the most promising method to generate xenogeneic organs. however, ethical issues prevent the study of human chimeras in the late embryonic stage of development. primate embryonic stem cells (escs), which have similar pluripotency to human escs, are a good model for studying interspecies chimerism and organ generation. however, whether primate escs can be used in xenogenous grafts remains unclear. in this study, ...202031781970
nomenclature report for killer-cell immunoglobulin-like receptors (kir) in macaque species: new genes/alleles, renaming recombinant entities and ipd-nhkir updates.the killer-cell immunoglobulin-like receptors (kir) are encoded by a diverse group of genes, which are characterized by allelic polymorphism, gene duplications, and recombinations, which may generate recombinant entities. the number of reported macaque kir sequences is steadily increasing, and these data illustrate a gene system that may match or exceed the complexity of the human kir cluster. this report lists the names of quality controlled and annotated kir genes/alleles with all the relevant ...202031781789
the effects of population tuning and trial-by-trial variability on information encoding and behavior.identifying the features of population responses that are relevant to the amount of information encoded by neuronal populations is a crucial step toward understanding population coding. statistical features, such as tuning properties, individual and shared response variability, and global activity modulations, could all affect the amount of information encoded and modulate behavioral performance. we show that two features in particular affect information: the modulation of population responses a ...202031754013
pharmacologic modulation of noxious stimulus-evoked brain activation in cynomolgus macaques observed with functional neuroimaging.maintaining effective analgesia during invasive procedures performed under general anesthesia is important for minimizing postoperative complications and ensuring satisfactory patient wellbeing and recovery. while patients under deep sedation may demonstrate an apparent lack of response to noxious stimulation, areas of the brain related to pain perception may still be activated. thus, these patients may still experience pain during invasive procedures. the current study used anesthetized or seda ...202031753062
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