Nonhuman Primate Studies Research Articles

Rational attenuation of canine distemper virus (CDV) to develop a morbillivirus animal model that mimics measles in humans.

Morbilliviruses are members of the family Paramyxoviridae and are known for their ability to cause systemic disease in a variety of mammalian hosts. The prototypic morbillivirus, measles virus (MeV), infects humans and still causes morbidity and mortality in unvaccinated children and young adults. Experimental infection studies in non-human primates have contributed to the understanding of measles pathogenesis. However, ethical restrictions call for the development of new animal models. Canine distemper virus (CDV) infects a wide range of animals, including ferrets, and its pathogenesis shares many features with measles. However, wild-type CDV infection is almost always lethal, while MeV infection is usually self-limiting. Here, we made five recombinant CDVs, predicted to be attenuated, and compared their pathogenesis to the non-attenuated recombinant CDV in a ferret model. Three viruses were insufficiently attenuated based on clinical signs, fatality, and systemic infection, while one virus was too attenuated. The last candidate virus caused a self-limiting infection associated with transient viremia and viral dissemination to all lymphoid tissues, was shed transiently from the upper respiratory tract, and did not result in acute neurological signs. Additionally, an in-depth phenotyping of the infected white blood cells showed lower infection percentages in all lymphocyte subsets when compared to the non-attenuated CDV. In conclusion, infection models using this candidate virus mimic measles and can be used to study pathogenesis-related questions and to test interventions for morbilliviruses in a natural host species.IMPORTANCEMorbilliviruses are transmitted via the respiratory route but cause systemic disease. The viruses use two cellular receptors to infect myeloid, lymphoid, and epithelial cells. Measles virus (MeV) remains an important cause of morbidity and mortality in humans, requiring animal models to study pathogenesis or intervention strategies. Experimental MeV infections in non-human primates are restricted by ethical and practical constraints, and animal morbillivirus infections in natural host species have been considered as alternatives. Inoculation of ferrets with wild-type canine distemper virus (CDV) has been used for this purpose, but in most cases, the virus overwhelms the immune system and causes highly lethal disease. Introduction of an additional transcription unit and an additional attenuating point mutation in the polymerase yielded a candidate virus that caused self-limiting disease with transient viremia and virus shedding. This rationally attenuated CDV strain can be used for experimental morbillivirus infections in ferrets that reflect measles in humans.

Physiologically based Pharmacokinetic Model Validated to Enable Predictions Of Multiple Drugs in a Long-acting Drug-combination Nano-Particles (DcNP): Confirmation with 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products

Drug-Combination Nanoparticles (DcNP) are a novel drug delivery system designed for synchronized delivery of multiple drugs in a single, long-acting, and targeted dose. Unlike depot formulations, slowly releasing drug at the injection site into the blood, DcNP allows multiple-drug-in-combination to collectively distribute from the injection site into the lymphatic system. Two distinct classes of long-acting injectables products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site. Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access as a part of the PBPK model validation. For clinical development, Class II long-acting drug-combination products, we leverage data from 3 nonhuman primate studies consisting of nine PK datasets: Study 1, varying fixed-dose ratios; Study 2, short multiple dosing with kinetic tails; Study 3, long multiple dosing (chronic). PBPK validation criteria were established to validate each scenario for all drugs. The models passed validation in 8 of 9 cases, specifically to predict Study 1 and 2, including PK tails, with ritonavir and tenofovir, fully passing Study 3 as well. PBPK model for lopinavir in Study 3 did not pass the validation due to an observable time-varying and delayed drug accumulation, which likely was due to ritonavir's CYP3A inhibitory effect building up during multiple dosing that triggered a mechanism-based drug-drug interaction (DDI). Subsequently, the final model enables us to account for this DDI scenario.

Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities?

Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.com) and collated preclinical and clinical studies for 17 marketed ONTs. In addition, clinical QTc data from 12 investigational ONTs were obtained from the literature. Of the marketed ONTs, eight were tested in the hERG assay with no inhibitory effect identified at the top concentration (range: 34-3,000 μM) tested. Fourteen of the ONTs were evaluated in nonhuman primate cardiovascular studies with 11 of them in dedicated telemetry studies. No effect on QTc intervals were observed (at high exposure multiples) in all studies. Clinically, four ONTs were evaluated in TQT studies; an additional six ONTs were assessed by concentration-QTc interval analysis, and six by routine safety electrocardiogram monitoring. None of the clinical studies identified a QTc prolongation risk; the same was true for the 12 investigational ONTs. A search of the FDA Adverse Event Database indicated no association between approved ONTs and proarrhythmias. Overall, the collective weight of evidence from 29 ONTs demonstrate no clinical proarrhythmic risk based on data obtained from ICH S7B/E14 studies. Thus, new ONTs may benefit from reduced testing strategies because they have no proarrhythmic risk, a similar cardiac safety profile as monoclonal antibodies, proteins, and peptides.

Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390.

The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (Kp,uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.

Nonclinical studies in non-human primates on ABX1100: A centyrin:Gys1 siRNA conjugate for the treatment of Pompe disease

Nonclinical studies in non-human primates on ABX1100: A centyrin:Gys1 siRNA conjugate for the treatment of Pompe disease

Dual-targeting CD33/CD123 NANOBODY T-cell engager with potent anti-AML activity and good safety profile

AbstractNovel therapies are needed for effective treatment of acute myeloid leukemia (AML). Relapse is common and salvage treatment with cytotoxic chemotherapy is rarely curative. CD123 and CD33, 2 clinically validated targets in AML, are jointly expressed on blasts and leukemic stem cells in >95% of patients with AML. However, their expression is heterogenous between subclones and between patients, which may affect the efficacy of single-targeting agents in certain patient populations. We present here a dual-targeting CD33/CD123 NANOBODY T-cell engager (CD33/CD123-TCE) that was designed to decrease the risk of relapse from possible single antigen-negative clones and to increase coverage within and across patients. CD33/CD123-TCE killed AML tumor cells expressing 1 or both antigens in vitro. Compared with single-targeting control compounds, CD33/CD123-TCE conferred equal or better ex vivo killing of AML blasts in most primary AML samples tested, suggesting a broader effectiveness across patients. In a disseminated cell-line–derived xenograft mouse model of AML, CD33/CD123-TCE cleared cancer cells in long bones and in soft tissues. As cytokine release syndrome is a well-documented adverse effect of TCE, the compound was tested in a cytokine release assay and shown to induce less cytokines compared to a CD123 single-targeting control. In an exploratory single-dose nonhuman primate study, CD33/CD123-TCE revealed a favorable PK profile. Depletion of CD123 and CD33 expressing cells was observed, but there were neither signs of cytokine release syndrome nor clinical signs of toxicity. Taken together, the CD33/CD123 dual-targeting NANOBODY TCE exhibits potent and safe anti-AML activity and promises a broad patient coverage.

“Dual‐pressure theory” in pathogenesis of glaucomatous optic neuropathy from the Beijing intracranial and intraocular pressure study

AbstractThe mechanical theory of glaucoma indicates that high intraocular pressure (IOP) leads to glaucomatous optic nerve damage. However, nearly half of primary open‐angle glaucoma patients with normal intraocular pressure also exhibit progression of what appears to be glaucomatous optic nerve damage. Our earlier prospective study identified for the first time that the relatively low intracranial pressure (ICP) is also an important risk factor for progressive glaucomatous injury of normal‐tension glaucoma. When considering the results of studies in nonhuman primates, clinical research, large‐scale natural‐population studies, and basic laboratory investigations, a new understanding of the pathophysiology of glaucoma, the “Dual‐Pressure Theory”, has been proposed. This theory states that “either high IOP or low ICP contributes to increasing the translaminar cribrosa pressure difference; it is the pressure difference rather than the IOP alone that results in the glaucomatous optic neuropathy”. Here, we provide a systematic introduction to Dual‐Pressure Theory relating to glaucoma, the form of a research map, an outline of basic laboratory investigations, the main methodology, and research updates.

Commentary: Early-in-life Isoflurane Exposure Alters Resting-State Functional Connectivity in Juvenile Non-human Primates - a Role for Neuroinflammation?

The concern about anesthesia-induced developmental neurotoxicity (AIDN) in infants and young children arises from animal studies indicating potential long-term neurobehavioral impairments following early-in-life anesthesia exposure. While initial clinical studies provided ambiguous results, recent prospective assessments in children indicate associations between early-in-life anesthesia exposure and later behavioral alterations. Ethical constraints and confounding factors in clinical studies pose challenges in establishing a direct causal link and in investigating its mechanisms. This commentary on a recent study in non-human primates (NHPs) focuses on exploring the role of neuroinflammation and alterations in brain functional connectivity in the behavioral impairments following early-in-life anesthesia exposure. In juvenile NHPs, chronic astrogliosis in the amygdala correlates with alterations in functional connectivity between this area with other regions of the brain and with the behavioral impairments, suggesting a potential mechanism for AIDN. Despite acknowledging the study's limitations, these findings emphasize the need for further research with larger cohorts to confirm these associations and to establish a causal link between the neuroinflammation and the behavioral alterations associated with early-in-life anesthesia exposure.

Evaluation of microglia activation related markers following a clinical course of TBS: A non-human primate study.

While the applicability and popularity of theta burst stimulation (TBS) paradigms remain, current knowledge of their neurobiological effects is still limited, especially with respect to their impact on glial cells and neuroinflammatory processes. We used a multimodal imaging approach to assess the effects of a clinical course of TBS on markers for microglia activation and tissue injury as an indirect assessment of neuroinflammatory processes. Healthy non-human primates received continuous TBS (cTBS), intermittent TBS (iTBS), or sham stimulation over the motor cortex at 90% of resting motor threshold. Stimulation was delivered to the awake subjects 5 times a week for 3-4 weeks. Translocator protein (TSPO) expression was evaluated using Positron Emission Tomography and [11C]PBR28, and myo-inositol (mI) and N-acetyl-aspartate (NAA) concentrations were assessed with Magnetic Resonance Spectroscopy. Animals were then euthanized, and immunofluorescence staining was performed using antibodies against TSPO. Paired t-tests showed no significant changes in [11C]PBR28 measurements after stimulation. Similarly, no significant changes in mI and NAA concentrations were found. Post-mortem TSPO evaluation showed comparable mean immunofluorescence intensity after active TBS and sham delivery. The current study suggests that in healthy brains a clinical course of TBS, as evaluated with in-vivo imaging techniques (PET and MRS), did not measurably modulate the expression of glia related markers and metabolite associated with neural viability.

RBD-Protein/Peptide Vaccine UB-612 Elicits Mucosal and Fc-Mediated Antibody Responses against SARS-CoV-2 in Cynomolgus Macaques.

Antibodies provide critical protective immunity against COVID-19, and the Fc-mediated effector functions and mucosal antibodies also contribute to the protection. To expand the characterization of humoral immunity stimulated by subunit protein-peptide COVID-19 vaccine UB-612, preclinical studies in non-human primates were undertaken to investigate mucosal secretion and the effector functionality of vaccine-induced antibodies in antibody-dependent monocyte phagocytosis (ADMP) and antibody-dependent NK cell activation (ADNKA) assays. In cynomolgus macaques, UB-612 induced potent serum-neutralizing, RBD-specific IgG binding, ACE2 binding-inhibition antibodies, and antibodies with Fc-mediated effector functions in ADMP and ADNKA assays. Additionally, immunized animals developed mucosal antibodies in bronchoalveolar lavage fluids (BAL). The level of mucosal or serum ADMP and ADNKA antibodies was found to be UB-612 dose-dependent. Our results highlight that the novel subunit UB-612 vaccine is a potent B-cell immunogen inducing polyfunctional antibody responses contributing to anti-viral immunity and vaccine efficacy.

Male-philopatric nonhuman primates and their potential role in understanding the evolution of human sociality.

In most primate species, males transfer out of their natal groups, resulting in groups of unrelated males. However, in a few species, including humans, males remain in their groups and form life-long associations with each other. This pattern of male philopatry is linked with cooperative male behaviors, including border patrols and predator defense. Because females in male-philopatric species form weaker kin networks with each other than in female-philopatric species, they are expected to evolve counter-strategies to male sexual coercion that are relatively independent of support from other females. Studies of male-philopatric nonhuman primates can provide insight into the evolutionary basis of prosocial behaviors, cooperation, and group action in humans and offer comparative models for understanding the sociality of other hominin species. This review will discuss patterns of dispersal and philopatry across primates, explore the resulting male and female behaviors, and argue that male-philopatric nonhuman primate species offer insight into the social and sexual dynamics of hominins throughout evolution.

Development and assessment of a stair ascension challenge as a measure of aging and physical function in nonhuman primates.

Nonhuman primates (NHPs) are valuable models for studying healthspan, including frailty development. Frailty metrics in people centers on functional measures, including usual gait speed which can be predictive of all-cause mortality. This concept that physical competencies are able to prognosticate an individual's health trajectory over chronologic aging is well-accepted and has led to refinements in how physical function is evaluated, and include measures of strength and power along with walking speed. NHP studies of aging require evaluation of physical function, which can be difficult in field and research settings. We compared stair climb velocity to usual walking speed in 28 peri-geriatric to geriatric NHPs, as incorporating a climbing obstacle integrates multiple components of physical function: isolated leg and back strength, proprioception, balance, and range of motion. We find that stair climbing speed was reliable between observers, and whether timing was in-person take from video capture. The stair climb rates were 50% more associated with chronological age than walking speed (R = -0.68 vs. -0.45) and only stair climbing speeds were retained as predictive of age when walking speed and bodyweight were included in multivariate models (overall R2 = 0.44; p < 0.0001). When comparing young (10-16 years) versus geriatric (16-29 years) stair climbing speed was significantly different (p < 0.001), while walking speeds only tended to be slower (p = 0.12) suggesting that the additional challenge of a stair climb better unmasks subclinical frailty development that usual walking speed.

Pre-saccadic Neural Enhancements in Marmoset Area MT.

Each time we make an eye movement, attention moves before the eyes, resulting in a perceptual enhancement at the target. Recent psychophysical studies suggest that this pre-saccadic attention enhances the visual features at the saccade target, whereas covert attention causes only spatially selective enhancements. While previous nonhuman primate studies have found that pre-saccadic attention does enhance neural responses spatially, no studies have tested whether changes in neural tuning reflect an automatic feature enhancement. Here we examined pre-saccadic attention using a saccade foraging task developed for marmoset monkeys (one male and one female). We recorded from neurons in the middle temporal area with peripheral receptive fields that contained a motion stimulus, which would either be the target of a saccade or a distracter as a saccade was made to another location. We established that marmosets, like macaques, show enhanced pre-saccadic neural responses for saccades toward the receptive field, including increases in firing rate and motion information. We then examined if the specific changes in neural tuning might support feature enhancements for the target. Neurons exhibited diverse changes in tuning but predominantly showed additive and multiplicative increases that were uniformly applied across motion directions. These findings confirm that marmoset monkeys, like macaques, exhibit pre-saccadic neural enhancements during saccade foraging tasks with minimal training requirements. However, at the level of individual neurons, the lack of feature-tuned enhancements is similar to neural effects reported during covert spatial attention.

XTX301, a Tumor-Activated Interleukin-12 Has the Potential to Widen the Therapeutic Index of IL12 Treatment for Solid Tumors as Evidenced by Preclinical Studies.

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain. In vitro characterization demonstrates multiple matrix metalloproteases, as well as human primary tumors cultured as cell suspensions, can effectively activate XTX301. Intravenous administration of a mouse surrogate mXTX301 demonstrated significant tumor growth inhibition (TGI) in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating TGI compared with non-activatable control molecules and the greater percentage of active mXTX301 in tumors versus other organs further confirms activation by the tumor microenvironment-associated proteases in vivo. Pharmacodynamic characterization shows tumor selective increases in inflammation and upregulation of immune-related genes involved in IFNγ cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a nonhuman primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent antitumor activity while widening the therapeutic index of IL12 treatment and is currently being evaluated in a phase I clinical trial.

EX103, a Novel CD20xCD3 Bispecific Antibody, Showed a Favorable Safety and Potent Single-Agent Antitumor Activity in Heavily Pretreated Relapsed/Refractory Patients with B-Cell Non-Hodgkin Lymphoma

Introduction Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States, and relapsed or refractory (R/R) B cell NHL had a poor prognosis. In recent years, T cell engaging bispecific antibody (TCB) emerged as a promising therapy. Nevertheless, severe cytokine release syndrome (CRS) remains to be a significant challenge in TCB treatment. To overcome this issue, we designed a new CD20xCD3 bispecific antibody (EX103) with a lower affinity to CD3. In the non-human primate tox study, EX103 induced much lower IL-6 release. Preliminary data from dose escalation part of Phase I clinical study demonstrates that EX103 has an encouraging safety and robust single-agent antitumor activity trend, even at low doses, in heavily pretreated R/R B-NHL patients. Method The dose-escalation part (8 dose cohorts, ranging from 1.2 to 36 mg) of this Phase I, multicenter, single-arm, open-label clinical trial has enrolled R/R CD20+ B-cell non-Hodgkin lymphoma subjects at 4 study sites in China. Objectives include safety, dose finding (RP2D), and antitumor activity. Eligible patients in each cohort received intravenous(iv) step-up doses of EX103 (with 1 priming dose and 2 intermediate doses followed by 1 target dose of EX103) administered in a 28-day dose limiting toxicity (DLT) observation period, and then received a target dose every 2 weeks for up to 12 cycles until disease progression or unacceptable toxicity. Response rates reported are based on the Lugano criteria (2014). Results As of June 2023, 5 cohorts (target dose from 1.2 to 18 mg) of the dose-escalation were completed. Among 13 evaluable patients , 9 of them are aggressive B-NHL (5 Diffuse large B-cell lymphoma (DLBCL), 3 Follicular lymphoma (FL) grade 3B, and 1 Mantle cell lymphoma (MCL)), 2 of them are indolent B-NHL (1 FL grade 1-3A, 1 Marginal zone lymphoma (MZL)), and 2 of them are Chronic lymphocytic leukemia (CLL). No DLT was observed, and the maximum tolerated dose (MTD) was not reached. The most common adverse events (AEs) were CRS, pyrexia, neutropenia, thrombocytopenia. All CRS were grade (Gr) 1-2, no Gr 3 or higher CRS. Most CRS events occurred in first or second treatment cycle, and all CRS related clinical symptoms were resolved within 48 hours. No Immune effector cell-associated neurotoxicity syndrome (ICANS) or other clinically significant neurologic AEs were reported. Among those patients, the median age was 51 years (range 43-66) and median number of prior lines of treatment was 5 (range 2-8). The preliminary Disease Control Rate (DCR) is 84.6% (11/13). Among 9 aggressive NHL patients, the overall response rate (ORR) was 67.7 % (6/9), including 3 DLBCL patients (1 each in 6 or 12 or 18 mg cohorts) and 1 MCL patient (in 3 mg cohort) achieving CR, and 2 grade 3B FL patients achieving PR (1 each in 6 or 18 mg cohorts). Both indolent NHL patients (1 FL (Grade 1-3A) and 1 MZL in 12 mg cohort) achieved PR and the preliminary ORR for indolent NHL was 100.0 % (2/2). Of 2 CLL patients, 1 achieved SD (3mg cohort). It is worth mentioning that two of the patients who failed prior CAR-T treatment had achieved PR after received 6-14 week treatment of EX103. Both patients are still under EX103 treatment. Conclusions Although this study has a limited number of subjects so far and the findings are preliminary, the available dose-escalation data demonstrate that single-agent EX103, even at low doses (3 or 6 mg), exhibits remarkable antitumor activity and favorable safety. Furthermore, EX103 demonstrates promising efficacy in heavily pretreated patients with R/R B-NHL, including some who have previously failed CAR-T treatment. The safety and efficacy of EX103 will be further evaluated in an ongoing clinical study.

1355. The SARS-CoV-2 Monoclonal Antibody AZD3152 Potently Neutralizes Historical and Emerging Variants and is Being Developed for the Prevention and Treatment of COVID-19 in High-risk Individuals

Abstract Background EVUSHELD was developed for the prevention and treatment of mild-to-moderate COVID-19 for high-risk individuals. However, the SARS-CoV-2 virus continues to evolve in the presence of natural- and vaccine-acquired immunity, escaping previously authorized antibody therapies such as bebtelovimab and EVUSHELD. AZD3152 was selected to neutralize all known SARS-CoV-2 variants of concern and is being developed to provide immunocompromised individuals with continued protection against SARS-CoV-2. Methods Structural analyses were performed to map the AZD3152 binding site. Neutralization assays were employed to determine the potency of AZD3152 across a panel of historical and emerging SARS-CoV-2 variants. Hamsters were prophylactically administered 6.7-60 mg/kg AZD3152 or a control antibody, then challenged intranasally with 6x103 PFU WA-1 SARS-CoV-2, then monitored for weight loss; lung viral load and pathology were evaluated at days 3 and 7. A 3 week GLP repeat IM and IV dose toxicity study in nonhuman primates (NHP) was performed. Results AZD3152 binds to a conserved epitope on the spike receptor binding domain and blocks ACE2 binding. AZD3152 potently neutralizes authentic viral variants (EC50 range, 8.3 to 110.9 ng/mL) and SARS-CoV-2 pseudoviruses (EC50 range of 3.2 to 25.0 ng/mL), including XBB.1.5. Prophylactic administration of AZD3152 conferred dose-dependent protection to hamsters following challenge. Even at a suboptimal dose of 6.7 mg/kg, &amp;lt; 5% weight loss and 2 logs reduction in lung viral subgenomic RNA were observed. AZD3152 was not associated with any adverse findings in NHP and the no observed-adverse-effect-level was the highest dose tested (150 mg/kg). Toxicokinetics demonstrated similar systemic exposure following IM and IV dosing with bioavailability of 94.9% and half-life range of 15.2-26.5 days by IM. Conclusion These results demonstrate that AZD3152 binds a conserved epitope resulting in broad neutralization of SARS-CoV-2 variants, protects hamsters from disease, and has a favorable safety profile in NHP. Thus, AZD3152 may serve as a next-generation antibody for the prevention and treatment of COVID-19. Disclosures Joseph R Francica, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yingyun Cai, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Seme Diallo, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kim Rosenthal, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kuishu Ren, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Daniel J. Flores, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Andrew Dippel, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yuling Wu, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Xiaoru Chen, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Erin Cantu, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Rakesh Choudhary, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Michal Sulikowski, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Hibret Adissu, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nydia van Dyk, MSc, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Vaheh Oganesyan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Saravanan Rajan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Patricia C. Ryan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yueh-Ming Loo, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Taylor Cohen, PhD, AstraZeneca: Employement|AstraZeneca: Stocks/Bonds Mark T. Esser, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Wade Blair, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds

The PREMISE database of 20 Macaca fascicularis PET/MRI brain images available for research

Non-human primate studies are unique in translational research, especially in neurosciences where neuroimaging approaches are the preferred methods used for cross-species comparative neurosciences. In this regard, neuroimaging database development and sharing are encouraged to increase the number of subjects available to the community, while limiting the number of animals used in research. Here we present a simultaneous positron emission tomography (PET)/magnetic resonance (MR) dataset of 20 Macaca fascicularis images structured according to the Brain Imaging Data Structure standards. This database contains multiple MR imaging sequences (anatomical, diffusion and perfusion imaging notably), as well as PET perfusion and inflammation imaging using respectively [15O]H2O and [11C]PK11195 radiotracers. We describe the pipeline method to assemble baseline data from various cohorts and qualitatively assess all the data using signal-to-noise and contrast-to-noise ratios as well as the median of intensity and the pseudo-noise-equivalent-count rate (dynamic and at maximum) for PET data. Our study provides a detailed example for quality control integration in preclinical and translational PET/MR studies with the aim of increasing reproducibility. The PREMISE database is stored and available through the PRIME-DE consortium repository.

Atypical Ebola Virus Disease in a Rhesus Macaque.

Ebola virus (EBOV)-Makona infected more than 30 000 people from 2013 to 2016 in West Africa, among them many health care workers including foreign nationals. Most of the infected foreign nationals were evacuated and treated in their respective home countries, resulting in detailed reports of the acute disease following EBOV infection as well as descriptions of symptoms now known as post-Ebola syndrome, which occurred months after the infection. Symptoms associated with this syndrome include uveitis and neurological manifestations. In 1 of our EBOV-Makona nonhuman primate (NHP) studies, 1 NHP was euthanized on day 28 after infection having completely recovered from the acute disease. During convalescence, this NHP developed neurological signs and acute respiratory distress requiring euthanasia. The organ tropism had changed with high virus titers in lungs, brain, eye, and reproductive organs but no virus in the typical target organs for acute EBOV infection. This in part reflects sequelae described for EBOV survivors albeit developing quicker after recovery from acute disease.

DDEL-01. UTILIZING SENSOR ARRAYS FOR INTRACRANIAL PRESSURE (ICP) RESPONSE TO CEREBROSPINAL FLUID (CSF) DRUG ADMINISTRATION, AND POTENTIAL IMPLICATIONS FOR PERSONALIZED CARE IN CNS METASTASES PATIENTS

Abstract BACKGROUND Patients with leptomeningeal carcinomatosis (LC) may have elevated intracranial pressure (ICP) due to LC cancer cells having the potential to obstruct the arachnoid granulations.,Given that LC treatment may involve intrathecal (IT) drug delivery, monitoring ICP may be important for safe IT drug delivery. The EnClear device is a novel CNS drug delivery device with both intracranial and intralumbar CSF access and single-use sensing arrays that measure ICP in these dual locations. METHODS This is a non-human primate (NHP) study on three healthy NHP subjects undergoing IT gene therapy via intracerebroventricular (ICV). The sensor arrays measured ICP before, during, and after ICV infusion in both intracranial and lumbar locations. Our goal was to compare individual subject pressure response to drug administration as well as to compare lumbar and cranial pressure waveforms for concordance. Pressure response was quantified as change in pressure (ΔP) following volume (ΔV) administration, known as intracranial elastance (ΔP/ΔV). RESULTS Significant correlations were observed between ventricular and lumbar ICP waveforms with an average of 0.88 correlation coefficient. Pressure measurements between subjects demonstrated variable response to identical infusion volumes, with maximum pressures ranging from 20 mmHg to 40 mmHg. Intracranial elastance was calculated for each subject during infusions and resulted in a range of 12 to 36 mmHg/mL, a 3-fold difference in elastance between subjects. CONCLUSION In healthy NHPs, changes to cranial volume and pressure response can be measured in the lumbar space with good correlation between the two measurement locations. Despite this consistency between these two locations on the same subject, intersubject variability was seen despite identical drug administration. Pressure waveform sensing systems can be incorporated in the future to enable clinicians to understand individual patient brain compliance and leverage this knowledge for personalized drug delivery, particularly in patients with LC.

Abstract 17013: CTX320: An Investigational in vivo CRISPR-Based Therapy Efficiently and Durably Reduces Lipoprotein (a) Levels in Non-Human Primates After a Single Dose

Background: Genetic and epidemiological studies have identified elevated levels of lipoprotein (a) (Lp(a)) as a direct cause of atherosclerosis and related diseases. CTX320™ is an investigational in vivo CRISPR/Cas9 gene editing therapy designed to knock out the apolipoprotein (a) component of Lp(a) in the liver. CTX320 contains Cas9 mRNA and guide RNA (gRNA) formulated for efficient encapsulation into LNPs for in vivo administration . Here we assessed the efficacy, safety, and durability of CTX320 in primary human cells and non-human primates (NHPs). Methods: For in vitro studies, primary human hepatocytes were plated and dosed with CTX320 one day later. Cells were harvested after three days and analyzed via Sanger and next-generation sequencing. For NHP studies, cynomolgus monkeys were dosed with either vehicle control or CTX320 at doses ranging from 0.5 to 3 mg/kg. Baseline levels of plasma Lp(a) were established via ELISA prior to dosing and plasma Lp(a) levels were measured at multiple intervals after dosing until the end of each study. Results: In primary human hepatocytes, potent, dose-dependent editing of up to &gt;80% was observed with CTX320. In NHPs, dose-dependent editing in the liver of ~10%, ~45%, and ~65% at the 0.5, 1.5, and 3 mg/kg doses, respectively, was observed after treatment with CTX320. Plasma Lp(a) levels were reduced by ~20%, ~80%, and ~90% from baseline in each of these respective groups. These reduced Lp(a) levels were attained by Day 15 and lasted for the duration of the study (Day 84). As is commonly observed with LNP delivery, transient elevation in liver enzymes was observed and resolved within 14 days without intervention. In a separate durability study in NHPs, a single infusion of CTX320 at 2 mg/kg led to significant and durable decreases in plasma Lp(a) levels. By Day 14, plasma Lp(a) levels had decreased by an average of 94% from baseline, which persisted through Day 224. The study is ongoing. Conclusion: CTX320 was well-tolerated in NHPs and resulted in high levels of editing in the liver that led to long-lasting reduction in plasma Lp(a). This data suggests CTX320 could be used to reduce plasma Lp(a) levels in humans.