Publications

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regulated intratumoral expression of il-12 using a rheoswitch therapeutic system® (rts®) gene switch as gene therapy for the treatment of glioma.the purpose of this study was to determine if localized delivery of il-12 encoded by a replication-incompetent adenoviral vector engineered to express il-12 via a rheoswitch therapeutic system® (rts®) gene switch (ad-rts-il-12) administered intratumorally which is inducibly controlled by the oral activator veledimex is an effective approach for glioma therapy. mice bearing 5-10-day-old intracranial gl-261 gliomas were intratumorally administered ad-rts-mil-12 in which il-12 protein expression is ...201829755109
discovery of benzimidazole derivatives as orally active renin inhibitors: optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile.we previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-n-(2-methylpropyl)-n-[(3s,5r)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. since 3 showed unacceptably low bioavailability (ba) in rats, structural modification, using sbdd and focused on physicochemical properties was conducted to improve its pk profile while maintaining renin inhibitory activity. conversion of the amino group attached at the 4-position of pyrimidine to methylene ...201829754833
young macaques (macaca fascicularis) preferentially bias attention towards closer, older, and better tool users.examining how animals direct social learning during skill acquisition under natural conditions, generates data for examining hypotheses regarding how transmission biases influence cultural change in animal populations. we studied a population of macaques on koram island, thailand, and examined model-based biases during interactions by unskilled individuals with tool-using group members. we first compared the prevalence of interactions (watching, obtaining food, object exploration) and proximity ...201829754253
persistence of vertebral growth plate cartilage in aged cynomolgus monkeys.growth plates at each end of vertebral bodies play a pivotal role in longitudinal spinal growth. epiphyseal closures are formed in adult humans. although monkeys are frequently employed in bone and disc research, the age of epiphyseal closure has not been well documented. in this study, histological analyses of lumbar vertebral end plates and the surrounding tissue were performed in 11 normal cynomolgus monkeys aged approximately 9 to 15 years, and unclosed growth plate cartilage was detected in ...201829750005
testicular microlithiasis in a clinically healthy cynomolgus monkey (macaca fascicularis).the present article describes an occurrence of testicular microlithiasis in a cynomolgus monkey from a routine regulatory toxicology study. the monkey was from a negative control group. microscopically, the lesion was characterized by multiple extracellular mineralized calculi within seminiferous tubular epithelia of both testes without any tissue reaction or abnormal condition such as cryptorchidism, testicular neoplasm, or hypogonadism. the present case is remarkable in that there is a paucity ...201829750004
a novel neural prosthesis providing long-term electrocorticography recording and cortical stimulation for epilepsy and brain-computer interface.objectivewireless technology is a novel tool for the transmission of cortical signals. wireless electrocorticography (ecog) aims to improve the safety and diagnostic gain of procedures requiring invasive localization of seizure foci and also to provide long-term recording of brain activity for brain-computer interfaces (bcis). however, no wireless devices aimed at these clinical applications are currently available. the authors present the application of a fully implantable and externally rechar ...201829749917
chitinase mrna levels determined by qpcr in crab-eating monkey (macaca fascicularis) tissues: species-specific expression of acidic mammalian chitinase and chitotriosidase.mice and humans express two active chitinases: acidic mammalian chitinase (amcase) and chitotriosidase (chit1). both chitinases are thought to play important roles in specific pathophysiological conditions. the crab-eating monkey (macaca fascicularis) is one of the most frequently used nonhuman primate models in basic and applied biomedical research. here, we performed gene expression analysis of two chitinases in normal crab-eating monkey tissues by way of quantitative real-time polymerase chai ...201829747453
hepatic histopathological changes and dysfunction in primates following exposure to organic arsenic diphenylarsinic acid.organic arsenic diphenylarsinic acid (dpaa[v]) accumulates at high concentrations in the liver of primates after its subchronic administration. however, no studies on the hepatic effects of organic arsenic compounds, including dpaa(v), on primates have been reported to date. to clarify the toxicokinetics of dpaa(v) in the liver of primates, hepatic tissue specimens were collected from cynomolgus monkeys (n = 32) at 5, 29, 170, and 339 days after repeated administration of dpaa(v) for 28 days. fo ...201829743440
nonclinical and clinical pharmacological characterization of the potent and selective cathepsin k inhibitor miv-711.cathepsin k is an attractive therapeutic target for diseases in which bone resorption is excessive such as osteoporosis and osteoarthritis (oa). the current paper characterized the pharmacological profile of the potent and selective cathepsin k inhibitor, miv-711, in vitro and in cynomolgus monkeys, and assessed translation to human based on a single dose clinical study in man.201829743078
efficient generation of cynomolgus monkey induced pluripotent stem cell-derived intestinal organoids with pharmacokinetic functions.in preclinical studies, the cynomolgus monkey (cm) model is frequently used to predict the pharmacokinetics of drugs in the human small intestine, because of its evolutionary closeness to humans. intestinal organoids that mimic the intestinal tissue have attracted attention in regenerative medicine and drug development. in this study, we generated intestinal organoids from cm induced pluripotent stem (cmips) cells and analyzed their pharmacokinetic functions. cmips cells were induced into the hi ...201829742964
safety of intra-articular transplantation of lentivirally transduced mesenchymal stromal cells for haemophilic arthropathy in a non-human primate.joint bleeding and resultant arthropathy are major determinants of quality of life in haemophilia patients. we previously developed a mesenchymal stromal cell (msc)-based treatment approach for haemophilic arthropathy in a mouse model of haemophilia a. here, we evaluated the long-term safety of intra-articular injection of lentivirally transduced autologous mscs in non-human primates. autologous bone-marrow-derived mscs transduced with a lentiviral vector expressing coagulation factor viii (fvii ...201829737459
seven years of experiences of preclinical experiments of xeno-heart transplantation of pig to non-human primate (cynomolgus monkey).the absolute shortage of donors compared with patients requiring transplantation is currently an unsolved problem, and the only possible solution may be xenotransplantation. to establish a successful clinical trial, a preclinical study using nonhuman primates is essential. starting in november 2011, our team initiated heterotopic abdominal heart xenotransplantation, the first in the republic of korea. we present here the initial 7-year results.201829731087
a big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans.although lack of efficacy is an important cause of late stage attrition in drug development the shortcomings in the translation of toxicities observed during the preclinical development to observations in clinical trials or post-approval is an ongoing topic of research. the concordance between preclinical and clinical safety observations has been analyzed only on relatively small data sets, mostly over short time periods of drug approvals. we therefore explored the feasibility of a big-data anal ...201829730448
translational pk-pd modeling analysis of mcla-128, a her2/her3 bispecific monoclonal antibody, to predict clinical efficacious exposure and dose.introduction mcla-128 is a bispecific monoclonal antibody targeting the her2 and her3 receptors. pharmacokinetics (pk) and pharmacodynamics (pd) of mcla-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. the aim of this study was to characterize the pk and pd of mcla-128 and to predict a safe starting dose and efficacious clinical dose for the first-in-human study. methods a pk-pd model was developed based on pk data from cynomolgus monkeys and tumor growth data from ...201829728897
species-specific involvement of integrin αiibβ3 in a monoclonal antibody ch12 triggers off-target thrombocytopenia in cynomolgus monkeys.ch12 is a novel humanized monoclonal antibody against epidermal growth factor receptor variant iii (egfrviii) for cancer treatment. unfortunately, in pre-clinical safety evaluation studies, acute thrombocytopenia was observed after administration of ch12 in cynomolgus monkeys, but not rats. more importantly, in vitro experiments found that ch12 can bind and activate platelets in cynomolgus monkey, but not human peripheral blood samples. cynomolgus monkey-specific thrombocytopenia has been report ...201829724685
fc engineering of anti-nectin-2 antibody improved thrombocytopenic adverse event in monkey.nectin-2 is a transmembrane glycoprotein which is involved in the process of ca2+-independent cell-cell adhesion. in our previous study, we have demonstrated that nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. furthermore, we discovered multiple anti-nectin-2 fully human monoclonal antibodies which inhibited tumor growth in in vivo subcutaneous xenograft models with antibody-dependent cellular cytotoxicity (adcc) as the ...201829723247
seminal simian immunodeficiency virus in chronically infected cynomolgus macaques is dominated by virus originating from multiple genital organs.the sexual transmission of viruses is responsible for the spread of multiple infectious diseases. although the human immunodeficiency virus (hiv)/aids pandemic remains fueled by sexual contacts with infected semen, the origin of virus in semen is still unknown. in a substantial number of hiv-infected men, viral strains present in semen differ from the ones in blood, suggesting that hiv is locally produced within the genital tract. such local production may be responsible for the persistence of h ...201829720516
molecular mechanisms for species differences in organic anion transporter 1, oat1: implications for renal drug toxicity.species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. for example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. in this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (anps), with orga ...201829720497
predicting human clearance of organic anion transporting polypeptide substrates using cynomolgus monkey: in vitro-in vivo scaling of hepatic uptake clearance.this work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (oatp) transporters. nine oatp substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence ...201829720472
effect of ex vivo-expanded recipient regulatory t cells on hematopoietic chimerism and kidney allograft tolerance across mhc barriers in cynomolgus macaques: erratum. 201829702539
polymeric nano-shielded islets with heparin-polyethylene glycol in a non-human primate model.intraportal pancreatic islet transplantation incurs huge cell losses during its early stages due to instant blood-mediated inflammatory reactions (ibmirs), which may also drive regulation of the adaptive immune system. therefore, a method that evades ibmir will improve clinical islet transplantation. we used a layer-by-layer approach to shield non-human primate (nhp) islets with polyethylene glycol (nano-shielded islets, nsis) and polyethylene glycol plus heparin (heparin nano-shielded islets; h ...201829698867
lack of transmission of chronic wasting disease to cynomolgus macaques.chronic wasting disease (cwd) is a fatal prion disease that can infect deer, elk, and moose. cwd was first recognized in captive deer kept in wildlife facilities in colorado from 1967 to 1979. cwd has now been detected in 25 u.s. states, 2 canadian provinces, south korea, norway, and finland. it is currently unknown if humans are susceptible to cwd infection. understanding the health risk from consuming meat and/or products from cwd-infected cervids is a critical human health concern. previous r ...201829695429
virus-encoded mirnas in ebola virus disease.ebola virus (ebov) is a negative-strand rna virus that replicates in the cytoplasm and causes an often-fatal hemorrhagic fever. ebov, like other viruses, can reportedly encode its own micrornas (mirnas) to subvert host immune defenses. mirnas are short noncoding rnas that can regulate gene expression by hybridizing to multiple mrnas, and viral mirnas can enhance viral replication and infectivity by regulating host or viral genes. to date, only one ebov mirna has been examined in human infection. ...201829691416
lack of human-like extracellular sortilin neuropathology in transgenic alzheimer's disease model mice and macaques.alzheimer's disease (ad) is a devastating neurodegenerative disorder bearing multiple pathological hallmarks suggestive of complex cellular/molecular interplay during pathogenesis. transgenic mice and nonhuman primates are used as disease models for mechanistic and translational research into ad; the extent to which these animal models recapitulate ad-type neuropathology is an issue of importance. putative c-terminal fragments from sortilin, a member of the vacuolar protein sorting 10 protein (v ...201829690919
spontaneous endometriosis in cynomolgus monkeys as a clinically relevant experimental model.does spontaneous endometriosis in cynomolgus monkeys have the characteristics required of a good experimental model?201829684118
activation of liver ampk with pf-06409577 corrects nafld and lowers cholesterol in rodent and primate preclinical models.dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (nash). therapeutic activators of the amp-activated protein kinase (ampk) have been proposed as a treatment for metabolic diseases; we show that the ampk β1-biased activator pf-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclini ...201829673898
nonclinical comparability studies of recombinant human arylsulfatase a addressing manufacturing process changes.recombinant human arylsulfatase a (rhasa) is in clinical development for the treatment of patients with metachromatic leukodystrophy (mld). manufacturing process changes were introduced to improve robustness and efficiency, resulting in higher levels of mannose-6-phosphate and sialic acid in post-change (process b) compared with pre-change (process a) rhasa. a nonclinical comparability program was conducted to compare process a and process b rhasa. all doses were administered intrathecally. phar ...201829672630
inhibition of sperm motility in male macaques with ep055, a potential non-hormonal male contraceptive.men have two practical choices for contraception; the condom which has a high typical use failure rate or vasectomy. new male hormonal and non-hormonal contraceptives are under development that target either the production of sperm (spermatogenesis) or the delivery of sperm. one particular target is the sperm protein eppin, which is present on the surface of human spermatozoa. ep055 is a small organic compound that targets eppin on the surface of sperm and inhibits motility. ep055 was tested in ...201829672554
the cynomolgus macaque natural history model of pneumonic tularemia for predicting clinical efficacy under the animal rule.francisella tularensis is a highly infectious gram-negative bacterium that is the etiologic agent of tularemia in animals and humans and a tier 1 select agent. the natural incidence of pneumonic tularemia worldwide is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (mcm) in human populations. development and licensure of tularemia therapeutics and vaccines need to occur under the food and drug administration's (fda's) animal rule ...201829670861
investigation of the mechanism of therapeutic protein-drug interaction between methotrexate and golimumab, an anti-tnfα monoclonal antibody.a prominent example of human therapeutic protein-drug interaction (tp-di) is between methotrexate (mtx) and anti-tnfα mabs. one plausible mechanism for this tp-di is through the pharmacodynamic effect of mtx on immunogenicity. however, there is no definitive evidence to substantiate this mechanism, and other competing hypotheses, such as mtx suppressing fcγri expression thereby affecting mab pk, have also been proposed. in order to understand this mechanism, a cynomolgus monkey study was conduct ...201829667047
questioning the extreme neurovirulence of monkey b virus (macacine alphaherpesvirus 1).monkey b virus (macacine alphaherpesvirus 1; bv) occurs naturally in macaques of the genus macaca, which includes rhesus and long-tailed (cynomolgus) monkeys that are widely used in biomedical research. bv is closely related to the human herpes simplex viruses (hsv), and bv infections in its natural macaque host are quite similar to hsv infections in humans. zoonotic bv is extremely rare, having been diagnosed in only a handful of north american facilities with the last documented case occurring ...201829666644
review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by fda in 2016 and 2017.details of embryo-fetal development (efd) studies were compiled for all fda drug approvals in 2016-17. rats and rabbits were used for 63% of small molecule (sm) drugs. the cynomolgus monkey was used for 47% of biopharmaceuticals. rodent studies using the clinical mab or animal homologue replaced monkey studies under some circumstances. efd studies were not required for anti-cancer drugs when the mode of action was associated with known developmental risk. one quarter of sm non-oncology drugs and ...201829660390
analysis of wild macaque stone tools used to crack oil palm nuts.the discovery of oil palm (elaeis guineensis) nut-cracking by wild long-tailed macaques (macaca fascicularis) is significant for the study of non-human primate and hominin percussive behaviour. up until now, only west african chimpanzees (pan troglodytes verus) and modern human populations were known to use stone hammers to crack open this particular hard-shelled palm nut. the addition of non-habituated, wild macaques increases our comparative dataset of primate lithic percussive behaviour focus ...201829657792
transplantation of neural progenitor cells expressing glial cell line-derived neurotrophic factor into the motor cortex as a strategy to treat amyotrophic lateral sclerosis.early dysfunction of cortical motor neurons may underlie the initiation of amyotrophic lateral sclerosis (als). as such, the cortex represents a critical area of als research and a promising therapeutic target. in the current study, human cortical-derived neural progenitor cells engineered to secrete glial cell line-derived neurotrophic factor (gdnf) were transplanted into the sod1g93a als rat cortex, where they migrated, matured into astrocytes, and released gdnf. this protected motor neurons, ...201829656478
extending human igg half-life using structure-guided design.engineering of antibodies for improved pharmacokinetics through enhanced binding to the neonatal fc receptor (fcrn) has been demonstrated in transgenic mice, non-human primates and humans. traditionally, such approaches have largely relied on random mutagenesis and display formats, which fail to address related critical attributes of the antibody, such as effector functions or biophysical stability. we have developed a structure- and network-based framework to interrogate the engagement of igg w ...201829947573
early-drug development in the era of immuno-oncology: are we ready to face the challenges?the classical development of drugs has progressively faded away, and we are currently in an era of seamless drug-development, where first-in-human trials include unusually big expansion cohorts in the search for early signs of activity and rapid regulatory approval. the fierce competition between different pharmaceutical companies and the hype for immune combinations obliges us to question the current way in which we are evaluating these drugs. in this review, we discuss critical issues and cave ...201829945232
molecular and functional characterization of udp-glucuronosyltransferase 1a in cynomolgus macaques.udp-glucuronosyltransferases (ugts) are drug-metabolizing enzymes essential for the metabolism of endogenous substrates and xenobiotics. molecular characteristics of ugts have been extensively investigated in humans, but in cynomolgus macaques, a non-human primate species widely used in drug metabolism studies, remain to be investigated. in this study, 12 ugt1a cdnas (ugt1a1, 1a2, 1a4a, 1a4b, 1a5a, 1a5b, 1a5c, 1a6, 1a7, 1a8, 1a9, and 1a10) were isolated and characterized in cynomolgus macaques. ...201829944869
the brain-penetrant clinical atm inhibitor azd1390 radiosensitizes and improves survival of preclinical brain tumor models.poor survival rates of patients with tumors arising from or disseminating into the brain are attributed to an inability to excise all tumor tissue (if operable), a lack of blood-brain barrier (bbb) penetration of chemotherapies/targeted agents, and an intrinsic tumor radio-/chemo-resistance. ataxia-telangiectasia mutated (atm) protein orchestrates the cellular dna damage response (ddr) to cytotoxic dna double-strand breaks induced by ionizing radiation (ir). atm genetic ablation or pharmacologic ...201829938225
farletuzumab, a monoclonal antibody directed against folate receptor alpha, shows no evidence of teratogenicity in cynomolgus monkeys.farletuzumab is a humanized monoclonal antibody targeting human folate receptor alpha, which is being developed as an anti-cancer drug. a non-human primate reproductive study was conducted to evaluate whether it could cause any embryonic or fetal abnormalities. farletuzumab was administered intravenously to pregnant cynomolgus monkeys (n = 16/group) at doses of 0 or 67.5 mg/kg once weekly during gestation day (gd) 20 through 97. c-section was performed on gd100 ± 2, and fetuses were evaluated fo ...201829928988
gut microbiome composition in non-human primates consuming a western or mediterranean diet.the mammalian gastrointestinal tract harbors a highly diverse and dynamic community of bacteria. the array of this gut bacterial community, which functions collectively as a fully unified organ in the host metabolism, varies greatly among different host species and can be shaped by long-term nutritional interventions. non-human primates, our close phylogenetic relatives and ancestors, provide an excellent model for studying diet-microbiome interaction; however, compared to clinical and rodent st ...201829922651
non-human papillomaviruses for gene delivery in vitro and in vivo.papillomavirus capsids are known to have the ability to package dna plasmids and deliver them both in vitro and in vivo. of all known papillomavirus types, human papillomaviruses (hpvs) are by far the most intensely studied. although hpvs work well as gene transfer vectors, their use is limited as most individuals are exposed to this virus either through a hpv vaccination or natural infection. to circumvent these constraints, we produced pseudovirions (psvs) of ten non-human papillomavirus types ...201829912929
reemergence of reston ebolavirus in cynomolgus monkeys, the philippines, 2015.in august 2015, a nonhuman primate facility south of manila, the philippines, noted unusual deaths of 6 cynomolgus monkeys (macaca fascicularis), characterized by generalized rashes, inappetence, or sudden death. we identified reston ebolavirus (restv) infection in monkeys by using serologic and molecular assays. we isolated viruses in tissues from infected monkeys and determined viral genome sequences. restv found in the 2015 outbreak is genetically closer to 1 of the 4 restvs that caused the 2 ...201829912712
soft transparent graphene contact lens electrodes for conformal full-cornea recording of electroretinogram.visual electrophysiology measurements are important for ophthalmic diagnostic testing. electrodes with combined optical transparency and softness are highly desirable, and sometimes indispensable for many ocular electrophysiology measurements. here we report the fabrication of soft graphene contact lens electrodes (graces) with broad-spectrum optical transparency, and their application in conformal, full-cornea recording of electroretinography (erg) from cynomolgus monkeys. the graces give highe ...201829899545
placental and fetal effects of onartuzumab, a met/hgf signaling antagonist, when administered to pregnant cynomolgus monkeys.onartuzumab is an engineered single arm, monovalent monoclonal antibody that targets the met receptor and prevents hepatocyte growth factor (hgf) signaling. knockout mice have clearly demonstrated that hgf/met signaling is developmentally critical. a pre- and postnatal development study (enhanced design) was conducted in cynomolgus monkeys to evaluate the potential developmental consequences following onartuzumab administration. control or onartuzumab, at loading/maintenance doses of 75/50 mg/kg ...201829893934
optimized adeno-associated viral-mediated human factor viii gene therapy in cynomolgus macaques.hemophilia a is a common hereditary bleeding disorder that is characterized by a deficiency of human blood coagulation factor viii (hfviii). previous studies with adeno-associated viral (aav) vectors identified two liver-specific promoter and enhancer combinations (e03.ttr and e12.a1at) that drove high level expression of a codon-optimized, b-domain-deleted hfviii transgene in a mouse model of the disease. this study further evaluated these enhancer/promoter combinations in cynomolgus macaques u ...201829890905
long-term toxicity, pharmacokinetics and immune effects of a recombinant adenovirus vaccine expressing human papillomavirus 16 e6 and e7 proteins (hpv16 e6e7-ad5 vac) in primates.this study aimed to: evaluate long-term toxicity and pharmacokinetic parameters; to identify the target organ of toxicity of a recombinant adenovirus vaccine expressing human papillomavirus 16 e6 and e7 proteins (hpv16 e6e7-ad5 vac) in primates; and to determine the specific immune response of this recombinant adenovirus vaccine.201829887967
utility of arterial blood gas, cbc, biochemistry and cardiac hormones as evaluation parameters of cardiovascular disease in nonhuman primates.cardiovascular disease (cvd) has a tremendous impact on the quality of life of humans. while experimental animals are valuable to medical research as models of human diseases, cardiac systems differ widely across various animal species. thus, we examined a cvd model in cynomolgus monkeys. laboratory primates are precious resources, making it imperative that symptoms of diseases and disorders are detected as early as possible. thus, in this study we comprehensively examined important indicators o ...201829887581
bioanalysis of sulprostone, a prostaglandin e2 analogue and selective ep3 agonist, in monkey plasma by liquid chromatography-tandem mass spectrometry.sulprostone is a potent prostaglandin e2 (pge2) analogue and one of the first identified selective g-protein-coupled receptor 3 (ep3) agonists. it has been investigated as a potential antiulcer agent and frequently used in the research of ep3 antagonist. to assist pharmacokinetic and pharmacodynamic studies, a rapid and sensitive lc-ms/ms method was developed and qualified for the quantitation of sulprostone in monkey plasma. using electrospray ionization mass spectrometry, an ammonium adduct in ...201829883889
efficacy of an inhaled il-13 antibody fragment in a model of chronic asthma.il-13 is an important cytokine implicated in the pathogenesis of allergic asthma and is an attractive target for an inhaled therapeutic.201829883204
simultaneous assessment of transporter-mediated drug-drug interactions using a probe drug cocktail in cynomolgus monkey.we aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion-transporting polypeptide (oatp)1b, breast cancer resistance protein (bcrp), p-glycoprotein (p-gp), and organic anion transporter (oat)3. pharmacokinetics of substrate cocktail consisting of pitavastatin (oatp1b substrate), rosuvastatin (oatp1b/bcrp/oat3), sulfasalazine (bcrp), and talinolol (p-gp) were obtain ...201829880631
discovery of novel pyrazole-based selective aldosterone synthase (cyp11b2) inhibitors: a new template to coordinate the heme-iron motif of cyp11b2.it is necessary for aldosterone synthase (cyp11b2) inhibitors to have both high potency and high selectivity over 11β-hydroxylase (cyp11b1), a critical enzyme for cortisol synthesis. previous studies have reported a number of cyp11b2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of cyp11b2; however, highly selective inhibitors of human cyp11b2 are still needed. to expand the selectivity in humans, we explored alternative templates and found that p ...201829878770
dosing optimization of ccr4 immunotoxin for improved depletion of ccr4+ treg in nonhuman primates.recently, we have developed a diphtheria toxin-based recombinant anti-human ccr4 immunotoxin for targeting ccr4+ tumors and tregs. in this study, we further optimized the dosing schedule for improved ccr4+ treg depletion. we have demonstrated that up to a 90% depletion was achieved and the depletion extended to approximately 2 weeks in the peripheral blood and more than 48 days in the lymph node at 25 μg·kg-1 , bid for 8 consecutive days in cynomolgus monkeys. expansion was observed including mo ...201829873181
evidence for sprouting of dopamine and serotonin axons in the pallidum of parkinsonian monkeys.this light and electron microscopie immunohistochemical quantitative study aimed at determining the state of the dopamine (da) and serotonin (5-ht) innervations of the internal (gpi) and external (gpe) segments of the pallidum in cynomolgus monkeys (macaca fascicularis) rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (mptp). in contrast to the prominent da denervation of striatum, the gpi in mptp monkeys was found to be markedly enriched in da (th+) a ...201829867377
development of mgd007, a gpa33 x cd3-bispecific dart protein for t-cell immunotherapy of metastatic colorectal cancer.we have developed mgd007 (anti-glycoprotein a33 x anti-cd3), a dart protein designed to redirect t cells to target gpa33 expressing colon cancer. the gpa33 target was selected on the basis of an antibody-based screen to identify cancer antigens universally expressed in both primary and metastatic colorectal cancer specimens, including putative cancer stem cell populations. mgd007 displays the anticipated-bispecific binding properties and mediates potent lysis of gpa33-positive cancer cell lines, ...201829866746
a novel fully human anti-cd47 antibody as a potential therapy for human neoplasms with good safety.strategies for targeting cd47 are becoming a hot spot of cancer immunotherapy. however the ubiquitous expression of cd47, especially on the rbc, makes the targeted therapy facing safety risk issues. so, how to balance the safety and efficacy during cd47 inhibition is currently a major question. we had reported an anti-cd47 antibody zf1 with potent anti-tumor effect. in this study, we further developed and assessed a novel fully human anti-cd47 antibody, amms4-g4, derived from zf1 using affinity ...201829864508
pharmacokinetics and pharmacodynamics of the cytolytic anti-cd38 human monoclonal antibody tak-079 in monkey - model assisted preparation for the first in human trial.we are studying the fully human, igg1λ cytolytic monoclonal antibody tak-079, which binds cd38. cd38 is expressed on plasma and natural killer (nk) cells constitutively and upregulated on subsets of b and t lymphocytes upon activation. tak-079 cross-reacts with cd38 expressed by cynomolgus monkeys and depletes subsets of nk, b, and t cells. therefore, safety and function of tak-079 was evaluated in this species, prior to clinical development, using bioanalytical, and flow cytometry assays. we po ...201829864242
post-exposure protection in mice against sudan virus by a two antibody cocktail.sudan virus (sudv) and ebola viruses (ebov) are both members of the ebolavirus genus and have been sources of epidemics and outbreaks for several decades. we present here the generation and characterization of cross-reactive antibodies to both sudv and ebov, which were produced in a cell-free system and protective against sudv in mice. a non-human primate, cynomolgus macaque, was immunized with viral-replicon particles expressing the glycoprotein of sudv-boniface (8a). two separate antibody frag ...201829861435
quantitative translational analysis of brain kynurenic acid modulation via irreversible kynurenine aminotransferase ii inhibition.kynurenic acid (kyna) plays a significant role in maintaining normal brain function, and abnormalities in kyna levels have been associated with various central nervous system disorders. confirmation of its causality in human diseases requires safe and effective modulation of central kyna levels in the clinic. the kynurenine aminotransferases (kat) ii enzyme represents an attractive target for pharmacologic modulation of central kyna levels; however, kat ii and kyna turnover kinetics, which could ...201829853495
the impact of septic stimuli on the systemic inflammatory response and physiologic insult in a preclinical non-human primate model of polytraumatic injury.established animal trauma models are limited in recapitulating the pathophysiology of human traumatic injury. herein, we characterize the physiologic insult and inflammatory response in two clinically relevant non-human primate (nhp) trauma models.201829849508
relationship between menarche and fertility in long-tailed macaques (macaca fascicularis).we attempted to elucidate female reproduction in long-tailed macaques (macaca fascicularis). these monkeys have a non-seasonal menstruation cycle, which makes them suitable subjects for studies in a variety fields including medical science and regenerative medicine. we analyzed individual breeding data including time of menarche, start of regular menstruation, and first pregnancy. these three events are related to the maturation of female long-tailed macaques. all research subjects were female l ...201829848903
vp1 amino acid residue 145 of enterovirus 71 is a key residue for its receptor attachment and resistance to neutralizing antibody during cynomolgus monkey infection.enterovirus 71 (ev71) is a causative agent of hand, foot, and mouth disease and sometimes causes severe or fatal neurological complications. the amino acid at vp1-145 determines the virological characteristics of ev71. viruses with glutamic acid (e) at vp1-145 (vp1-145e) are virulent in neonatal mice and transgenic mice expressing human scavenger receptor b2, whereas those with glutamine (q) or glycine (g) are not. however, the contribution of this variation to pathogenesis in humans is not full ...201829848582
investigation into the mechanism(s) that leads to platelet decreases in cynomolgus monkeys during administration of isis 104838, a 2'-moe-modified antisense oligonucleotide.isis 104838, a 2'-o-methoxyethyl (2'-moe)-modified antisense oligonucleotide (aso), causes a moderate, reproducible, dose-dependent, but selflimiting decrease in platelet (plt) counts in monkeys and humans. to determine the etiology of plt decrease in cynomolgus monkeys, a 12-week repeat dose toxicology study in 5 cynomolgus monkeys given subcutaneous injections of isis 104838 (30-60 mg/kg/week). monkeys were also injected intravenously with 111indium(in)-oxine-labeled plts to investigate plt se ...201829846725
superparamagnetic iron oxide-enhanced magnetic resonance imaging of spontaneous hepatic neoplasia in a cynomolgus macaque (macaca fascicularis).although the number of reports describing tumors in aged nhp has increased, spontaneous neoplasias in nhp are extremely rare, with the notable exception of prosimians, in which spontaneous hepatic neoplasms arise. in addition to radiography and ultrasonography, superparamagnetic iron oxide (spio)-enhanced mri tends to be applied in human practice to non-invasively locate, identify, and size liver tumors and to define the border between neoplastic and normal tissues. here we report a 13-y-old fem ...201829843863
performance assessment of new urinary translational safety biomarkers of drug-induced renal tubular injury in tenofovir-treated cynomolgus monkeys and beagle dogs.newer urinary protein kidney safety biomarkers can outperform the conventional kidney functional biomarkers blood urea nitrogen (bun) and serum creatinine (scr) in rats. however, there is far less experience with the relative performance of these biomarkers in dogs and nonhuman primates. here, we report urine protein biomarker performance in tenofovir-treated cynomolgus monkeys and beagle dogs. tenofovir intravenous daily dosing in monkeys for 2 or 4 weeks at 30 mg/kg/day resulted in minimal to ...201829807506
nonclinical safety and pharmacokinetics of miglyol 812: a medium chain triglyceride in exenatide once weekly suspension.exenatide, a glucagon-like peptide-1 receptor agonist was originally developed as either a twice daily or once weekly injectable therapeutic for patients with type 2 diabetes. exenatide qw suspension was developed for use with an autoinjector device, in which the microspheres are suspended in miglyol 812, a mixture of medium chain triglycerides (mcts). mcts are a class of lipids whose fatty acid chains contain from six to 12 carbon atoms (medium chain fatty acids or mcfas). while mcts are edible ...201829806696
komodo dragon predation on crab-eating macaques at the rinca island's visitor centre, indonesia.we investigated the proportion of crab-eating macaques in the diet of komodo dragons and quantified the spatial habitat use between the species as a proxy for predation threat and in relation to prey availability due to ecotourism. in 2013, in loh buaya valley of rinca island, komodo national park, we conducted macroscopic identification of hairs, claws, dentition and osteological remains of consumed prey. for habitat use, we quantified the use of vertical strata by macaques through focal animal ...201830114686
a method for expansion of t cells from cynomolgus monkey (macaca fascicularis).t cells have been successfully applied to cancer immunotherapy. however, a challenge is an expansion of t cells from cynomolgus monkey, which is a valuable non-human primate model for t cell therapy transferring to the clinic. here, we compared several strategies to expand cynomolgus monkey t cell and developed an appropriate method. our study demonstrated that 100 ng/ml cd3 mab + 1% pha+ 1000 u/ml il2 therapy significantly expanded peripheral blood cd3+ t cells without compromising t cell pheno ...201830112696
lead concentration in long-tailed macaque (macaca fascicularis) hair in kuala selangor, malaysia.long-tailed macaque (macaca fascicularis) has the potential to be a good biological indicator for toxic exposure because they have an almost similar physiology and behaviour to humans. the objective of this study is to determine the concentration of lead (pb) in hair samples of long-tailed macaques which were found in and out of the kuala selangor nature park (ksnp) area. the hypothesis is long-tailed macaques that live in the anthropogenic area (outside ksnp) may be exposed to high levels of le ...201830112148
acute-phase cd4+ t cell responses targeting invariant viral regions are associated with control of live attenuated simian immunodeficiency virus.we manipulated sivmac239δnef, a model of major histocompatibility complex (mhc)-independent viral control, to evaluate characteristics of effective cellular responses mounted by mauritian cynomolgus macaques (mcms) that express the m3 mhc haplotype, which has been associated with poor control of pathogenic simian immunodeficiency virus (siv). we created sivδnef-8x to test the hypothesis that effective siv-specific t cell responses targeting invariant viral regions can emerge in the absence of im ...201830111562
gingival exudatome dynamics implicate inhibition of the alternative complement pathway in the protective action of the c3 inhibitor cp40 in nonhuman primate periodontitis.periodontitis is a prevalent chronic inflammatory disease associated with dysbiosis. although complement inhibition has been successfully used to treat periodontitis in animal models, studies globally analyzing inflamed tissue proteins to glean insight into possible mechanisms of action are missing. using quantitative shotgun proteomics, we aimed to investigate differences in composition of inflammatory gingival tissue exudate ("gingival crevicular fluid"; gcf), before and after local administra ...201830111112
single-axon tracing of the corticosubthalamic hyperdirect pathway in primates.individual axons that form the hyperdirect pathway in macaca fascicularis were visualized following microiontophoretic injections of biotinylated dextran amine in layer v of the primary motor cortex (m1). twenty-eight singly labeled axons were reconstructed in 3d from serial sections. the m1 innervation of the subthalamic nucleus (stn) arises essentially from collaterals of long-ranged corticofugal axons en route to lower brainstem regions. typically, after leaving m1, these large caliber axons ...201830109491
development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria.phenylketonuria (pku) is a genetic disease that is characterized by an inability to metabolize phenylalanine (phe), which can result in neurotoxicity. to provide a potential alternative to a protein-restricted diet, we engineered escherichia coli nissle to express genes encoding phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. administration of our synthetic strain, synb1618, to the pahenu2/enu2 pku mouse model reduced blood phe concentration by 38% compared with t ...201830102294
nonclinical safety assessment of cfz533, a fc-silent anti-cd40 antibody, in cynomolgus monkeys.cfz533 is a pathway blocking, nondepleting anti-cd40 antibody that is in clinical development for inhibition of transplant organ rejection and therapy for autoimmune diseases. a 26-week glp toxicity study in sexually mature cynomolgus monkeys was conducted in order to support chronic application of cfz533. cfz533 was subcutaneously administered at doses up to 150 mg/kg/week and was safe and generally well tolerated. cfz533 showed no adverse effects for cardiovascular, respiratory, and neurobehav ...201830099540
a novel highly potent and selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, inu-101.11β-hydroxysteroid dehydrogenase type 1 (11β-hsd1) is a cortisol regenerating enzyme that amplifies tissue glucocorticoid levels, especially in the liver and adipose tissue. knockout mice or a selective inhibitor of 11β-hsd1 improves metabolic syndrome parameters in preclinical models and human clinical trials. here, we evaluated the therapeutic potential of inu-101, a potent and selective oral inhibitor of 11β-hsd1. the in vitro activity of 11β-hsd1 was measured using the homogeneous time-resol ...201830096297
dissociation of lfp power and tuning in the frontal cortex during memory.working memory, the ability to maintain and manipulate information in the brain, is critical for cognition. during the memory period of spatial memory tasks, neurons in the prefrontal cortex code for memorized locations via persistent, spatially tuned increases in activity. local field potentials (lfps) are understood to reflect summed synaptic activity of local neuron populations and may offer a window into network-level processing. we recorded lfps from areas 8a and 9/46 while two male cynomol ...201830093534
development and characterization of a model for inducing fetal hemoglobin production in cynomolgus macaques (macaca fasicularis).hydroxyurea induces production of fetal hemoglobin (hbf), a tetramer of α and γ globin proteins and corresponding heme molecules, normally found in less than 1% of adult rbc. increases in circulating hbf are correlated with clinical improvement of patients with hemoglobinopathies, and hydroxyurea, as a daily medication, is the standard treatment for sickle cell anemia. although olive baboons (papio anubis) are considered a key model species for hbf induction, cynomolgus macaques (macaca fasicula ...201830092854
letter to the editor regarding "spontaneous findings in the eyes of cynomolgus monkeys ( macaca fascicularis) of mauritian origin" by woicke et al. ( toxicol pathol 46, 273-282, 2018). 201830092740
effects of unilateral electroacupuncture on bilateral proprioception in a unilateral anterior cruciate ligament injury model.background anterior cruciate ligament (acl) injury can cause knee proprioception degeneration, on which the electroacupuncture (ea) treatment has a definite effect. however, it is still not clear whether conducting ea intervention on the injured side can promote bilateral proprioception recovery. material and methods we randomly selected 6 of 9 normal cynomolgus monkeys to develop unilateral acl injury models via arthroscopy. all knees were divided into 5 groups: the normal control (nc) group, i ...201830082677
dosikit, a new immunoassay for fast radiation biodosimetry of hair and blood samples.dosikit is a field radiation biodosimetry immunoassay for fast triage of individuals exposed to external total-body or partial-body irradiation (tbi or pbi). assay proof-of-concept based on γ-h2ax analysis of human blood samples has been previously described as a promising tool for rapid assessment of tbi. here, we report on the performance of the assay for pbi based on an analysis of hair follicles irradiated with a 137cs gamma-ray source, at doses ranging from 0 to 20 gy and dose rates ranging ...201830074847
mycobacterium tuberculosis erdman infection of cynomolgus macaques of chinese origin.nearly one-third of the population worldwide is estimated to have latent tuberculosis infection (ltbi), which represents a vast reservoir for a constant source of tuberculosis (tb) transmission. it has been suggested that cynomolgus macaques are less susceptible to mycobacterium tuberculosis (m.tb) infection than rhesus macaques, we examined m.tb infection of chinese cynomolgus macaques.201830069358
persistent marburg virus infection in the testes of nonhuman primate survivors.sexual transmission of filoviruses was first reported in 1968 after an outbreak of marburg virus (marv) disease and recently caused flare-ups of ebola virus disease in the 2013-2016 outbreak. how filoviruses establish testicular persistence and are shed in semen remain unknown. we discovered that persistent marv infection of seminiferous tubules, an immune-privileged site that harbors sperm production, is a relatively common event in crab-eating macaques that survived infection after antiviral t ...201830173956
oocyte retrieval after heterotopic transplantation of ovarian tissue cryopreserved by closed vitrification protocol.a device for closed vitrification was designed to reduce the risk of contamination and investigated on its efficacy for ovarian function recovery after cryopreservation and heterotopic transplantation.201830173352
effects of gs-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis.spleen tyrosine kinase (syk) mediates signal transduction in multiple hematopoietic cells, including platelets. syk signals downstream of immunoreceptors and syk inhibition may ameliorate disease pathology in multiple autoimmune disorders; however, the impact of syk inhibition in platelets and its potential relevance to bleeding is not fully understood. these studies evaluated the effect of an oral syk inhibitor, gs-9876, on platelets in vitro and in vivo, and the impact of gs-9876 plus non-ster ...201830172129
genetic variants of glutathione s-transferase gstt1 and gstt2 in cynomolgus macaques: identification of gstt substrates and functionally relevant alleles.glutathione s-transferase (gst) is a family of important drug-metabolizing enzymes, conjugating endogenous and exogenous compounds. genetic polymorphisms result in the inter-individual variability of gst activity in humans. especially, human gstt1 and gstt2 null alleles are associated with toxicity and various cancers derived from chemicals. cynomolgus macaque, a nonhuman primate species widely used in drug metabolism studies, has molecular and enzymatic similarities of gsts to the human ortholo ...201830169019
ontogenetic changes to muscle architectural properties within the jaw-adductor musculature of macaca fascicularis.changes to soft- and hard-tissue components of the masticatory complex during development can impact functional performance by altering muscle excursion potential, maximum muscle forces, and the efficiency of force transfer to specific bitepoints. within macaca fascicularis, older individuals exploit larger, more mechanically resistant food items and more frequently utilize wide-gape jaw postures. we therefore predict that key architectural and biomechanical variables will scale during ontogeny ...201830168867
nonhuman primate model of persistent erectile and urinary dysfunction following radical prostatectomy: feasibility of minimally invasive therapy.persistent urinary incontinence (ui) and/or erectile dysfunction (ed) occur in 30-50% of post-radical prostatectomy patients regardless of nerve sparing approaches. identification of potential treatment options for these patients will require testing in an animal model that develops these chronic conditions. the objective was to characterize a nonhuman primate (nhp) model of persistent post-prostatectomy ed and ui and then test the feasibility of periurethral injection of the chemokine cxcl-12.201830168617
dna-based determination of ancestry in cynomolgus macaques (macaca fascicularis).interest in the genetic composition of cynomolgus macaques (macaca fascicularis) has increased due to the rising demand for nhp models in human biomedical research. significant genetic differences among regional populations of cynomolgus macaques can confound interpretations of research results because they do not solely reflect differences in experimental treatment effects. therefore, the common origin of cynomolgus macaques used as research subjects should be verified by using region-specific ...201830165920
comparison of cellular localisation of the ca2+ -binding proteins calbindin, calretinin and parvalbumin in the retina of four different macaca species.ca2+ -binding proteins are differentially expressed in the nervous system; their functional role often remains unclear. this immunohistochemical study aimed at characterising and comparing the expression pattern of the ca2+ -binding proteins calbindin (calb), calretinin (calr) and parvalbumin (parv) in the retina of four species of macaque monkeys: macaca fascicularis (cynomolgus macaque), m. mulatta (rhesus macaque), m. thibetana (tibetan macaque) and m. fuscata (japanese macaque). calb was fou ...201830155916
renal ischemia-reperfusion injury in a diabetic monkey model and therapeutic testing of human bone marrow-derived mesenchymal stem cells.clinically, acute kidney injury (aki) episodes in diabetes mellitus (dm) patients are associated with a cumulative risk of developing end-stage renal disease. in this study, we asked whether the severity of aki induced by renal ischemia-reperfusion injury (iri) is more prominent in dm than in non-dm control using a cynomolgus monkey (macaca fascicularis) model. we also investigated whether human bone marrow-derived mesenchymal stem cells (hbm-mscs) infused via the renal artery could ameliorate r ...201830155487
impact of ring size and drug loading on the pharmacokinetics of a combination dapivirine-darunavir vaginal ring in cynomolgus macaques.this work investigates the impact of vaginal ring size and drug loading on the in vitro release, safety, ease of fit, and pharmacokinetics in cynomolgus macaques of matrix-type silicone elastomer vaginal rings containing a combination of the non-nucleoside reverse transcriptase inhibitor dapivirine and the protease inhibitor darunavir. drug-free and drug-loaded vaginal rings having three different geometries were manufactured by reaction injection molding. in vitro drug release was assessed usin ...201830153490
mucosal antibody responses to vaccines targeting siv protease cleavage sites or full-length gag and env proteins in mauritian cynomolgus macaques.hiv mutates rapidly and infects cd4+ t cells, especially when they are activated. a vaccine targeting conserved, essential viral elements while limiting cd4+ t cell activation could be effective. learning from natural immunity observed in a group of highly hiv-1 exposed seronegative kenyan female sex workers, we are testing a novel candidate hiv vaccine targeting the 12 viral protease cleavage sites (pcss) (the pcs vaccine), in comparison with a vaccine targeting full-length gag and env (the gag ...201830153293
vaccine-mediated induction of an ebolavirus cross-species antibody binding to conserved epitopes on the glycoprotein heptad repeat 2/membrane-proximal external junction.the membrane-proximal external regions (mper) of the human immunodeficiency virus envelope glycoprotein (gp) generate broadly reactive antibody responses and are the focus of vaccine development efforts. the conservation of amino acids within filovirus gp heptad repeat region (hr)2/mper suggests that it may also represent a target for a pan-filovirus vaccine. we immunized a cynomolgus macaque against ebola virus (ebov) using a deoxyribonucleic acid/adenovirus 5 prime/boost strategy, sequenced me ...201830137549
establishment of a macaca fascicularis gut microbiome gene catalog and comparison with the human, pig, and mouse gut microbiomes.macaca fascicularis, the cynomolgus macaque, is a widely used model in biomedical research and drug development as its genetics and physiology are close to those of humans. detailed information on the cynomolgus macaque gut microbiota, the functional interplay between the gut microbiota and host physiology, and possible similarities to humans and other mammalians is very limited. the aim of this study was to construct the first cynomolgus macaque gut microbial gene catalog and compare this catal ...201830137359
sirt6 deficiency results in developmental retardation in cynomolgus monkeys.sirt6 acts as a longevity protein in rodents1,2. however, its biological function in primates remains largely unknown. here we generate a sirt6-null cynomolgus monkey (macaca fascicularis) model using a crispr-cas9-based approach. sirt6-deficient monkeys die hours after birth and exhibit severe prenatal developmental retardation. sirt6 loss delays neuronal differentiation by transcriptionally activating the long non-coding rna h19 (a developmental repressor), and we were able to recapitulate thi ...201830135584
two vaccines for staphylococcus aureus induce a b-cell-mediated immune response.staphylococcus aureus causes severe disease in humans for which no licensed vaccine exists. a novel s. aureus vaccine (sa4ag) is in development, targeting the capsular polysaccharides (cps) and two virulence-associated surface proteins. vaccine-elicited antibody responses to cps are efficacious against serious infection by other encapsulated bacteria. studies of natural s. aureus infection have also shown a role for th17 and/or th1 responses in protection. single-antigen vaccines, including cps, ...201830135219
intrathecal delivery of human esc-derived mesenchymal stem cell spheres promotes recovery of a primate multiple sclerosis model.nonhuman primate experimental autoimmune encephalomyelitis (eae) is a valuable model for multiple sclerosis, an inflammatory demyelinating disease in the central nervous system (cns). human embryonic stem cell-derived mesenchymal stem cells (emsc) are effective in treating murine eae. yet, it remains unknown whether the emsc efficacy is translatable to humans. here we induced a primate eae model in cynomolgus monkeys and delivered emsc in spheres (emscsp) to preserve the cell viability during lo ...201830131877
generation and characterization of a high affinity anti-human fcrn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma igg concentration.rozanolixizumab (ucb7665), a humanized high-affinity anti-human neonatal fc receptor (fcrn) monoclonal antibody (igg4p), has been developed to reduce pathogenic igg in autoimmune and alloimmune diseases. we document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. we report activity data for rozanolixizumab and the different molecular formats in human cells, fcrn-transgenic mice, and cynomolgus monkeys. rozano ...201830130439
detection of complement activators in immune attack eyes after ips-derived retinal pigment epithelial cell transplantation.to determine whether human induced pluripotent stem (ips) cell-derived retinal pigment epithelial (rpe) cells (ips-rpe) can express complement factors.201830128491
comparison of inhibitory neuromuscular transmission in the cynomolgus monkey ias and rectum: special emphasis on differences in purinergic transmission.inhibitory neuromuscular transmission (nmt) was compared in the internal anal sphincter (ias) and rectum of the cynomolgus monkey, an animal with high gene sequence identity to humans. nitrergic nmt was present in both muscles while purinergic nmt was limited to the rectum and vipergic nmt to the ias. the profile for monkey ias more closely resembles humans than rodents. in both muscles, sk3 channels were localized to pdgfrα+ cells that were closely associated with nnos+ /vip+ nerves. gene expre ...201830198065
comparison of efficacy and toxicity between botulinum toxin subtypes a1 and a2 in cynomolgus macaques.botulinum toxin type a (subtype a1) is used as therapeutic agent for some neurological disorders causing spasticity. the toxin products have an upper dosage limit, and their adverse events, such as side effects of diffusion following high-dose administration, have become serious issues. therefore, a preparation with greater therapeutic efficacy at lower dosages and less diffusion in the body is desired. we have attempted to produce neurotoxin derived from subtype a2 (a2ntx), which has a differen ...201830193802
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