Abstract P003: In vitro and in vivo characterization of CCR8 humanized mouse model (HuGEMM™)

ABSTRACT A series of 4-amino 2-anilinoquinazolines optimized for activity against the most lethal malaria parasite of humans, Plasmodium falciparum, was evaluated for activity against other human Plasmodium parasites and related apicomplexans that infect humans and animals. Four of the most promising compounds from the 4-amino 2-anilinoquinazoline series were equally as effective against the asexual blood stages of the zoonotic P. knowlesi, suggesting that they could also be effective against the closely related P. vivax, another important human pathogen. The 2-anilinoquinazoline compounds were also potent against an array of P. falciparum parasites resistant to clinically available antimalarial compounds, although slightly less so than against the drug-sensitive 3D7 parasite line. The apicomplexan parasites Toxoplasma gondii, Babesia bovis, and Cryptosporidium parvum were less sensitive to the 2-anilinoquinazoline series with a 50% effective concentration generally in the low micromolar range, suggesting that the yet to be discovered target of these compounds is absent or highly divergent in non-Plasmodium parasites. The 2-anilinoquinazoline compounds act as rapidly as chloroquine in vitro and when tested in rodents displayed a half-life that contributed to the compound’s capacity to clear P. falciparum blood stages in a humanized mouse model. At a dose of 50 mg/kg of body weight, adverse effects to the humanized mice were noted, and evaluation against a panel of experimental high-risk off targets indicated some potential off-target activity. Further optimization of the 2-anilinoquinazoline antimalarial class will concentrate on improving in vivo efficacy and addressing adverse risk.

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Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356

Journal of Virology ◽

10.1128/jvi.01830-18 ◽

2019 ◽

Vol 93 (8) ◽

Cited By ~ 3

Author(s):

Wenzhong Wei ◽

Joshua Wiggins ◽

Duoyi Hu ◽

Vladimir Vrbanac ◽

Dane Bowder ◽

...

Keyword(s):

Mouse Model ◽

Lactobacillus Acidophilus ◽

Sexual Transmission ◽

Effective Vaccine ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

Antiviral Proteins ◽

Hiv 1

ABSTRACT Lactobacillus bacteria are potential delivery vehicles for biopharmaceutical molecules because they are well-recognized as safe microorganisms that naturally inhabit the human body. The goal of this study was to employ these lactobacilli to combat human immunodeficiency virus type 1 (HIV-1) infection and transmission. By using a chromosomal integration method, we engineered Lactobacillus acidophilus ATCC 4356 to display human CD4, the HIV-1 receptor, on the cell surface. Since human CD4 can bind to any infectious HIV-1 particles, the engineered lactobacilli can potentially capture HIV-1 of different subtypes and prevent infection. Our data demonstrate that the CD4-carrying bacteria are able to adsorb HIV-1 particles and reduce infection significantly in vitro and also block intrarectal HIV-1 infection in a humanized mouse model in preliminary tests in vivo. Our results support the potential of this approach to decrease the efficiency of HIV-1 sexual transmission. IMPORTANCE In the absence of an effective vaccine, alternative approaches to block HIV-1 infection and transmission with commensal bacteria expressing antiviral proteins are being considered. This report provides a proof-of-concept by using Lactobacillus bacteria stably expressing the HIV-1 receptor CD4 to capture and neutralize HIV-1 in vitro and in a humanized mouse model. The stable expression of antiviral proteins, such as CD4, following genomic integration of the corresponding genes into this Lactobacillus strain may contribute to the prevention of HIV-1 sexual transmission.

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In Vitro and In Vivo Characterization of Ultraviolet Light C-Irradiated Human Platelets in a 2 Event Mouse Model of Transfusion

PLoS ONE ◽

10.1371/journal.pone.0079869 ◽

2013 ◽

Vol 8 (11) ◽

pp. e79869 ◽

Cited By ~ 5

Author(s):

Li Zhi ◽

Xuan Chi ◽

Jaroslav G. Vostal

Keyword(s):

Mouse Model ◽

Ultraviolet Light ◽

Human Platelets ◽

In Vivo Characterization

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Faculty Opinions recommendation of Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736379003.793564790 ◽

2019 ◽

Author(s):

Nathaniel Landau

Keyword(s):

T Cells ◽

Antiviral Activity ◽

Mouse Model ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

Infected Cells ◽

Anti Hiv

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A donor-dependent in vivo model for single agent and drug combination cytokine release syndrome safety evaluation.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2612 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2612-2612

Author(s):

James G. Keck ◽

Mingshan Cheng ◽

Michael Brehm ◽

Dale Greiner ◽

Lenny J. Shultz ◽

...

Keyword(s):

Mouse Model ◽

Single Agent ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Humanized Mouse ◽

Humanized Mouse Model ◽

Human Pbmc ◽

Cytokine Levels

2612 Background: Although antibodies and CART cells therapies have been successfully used for cancer therapy, they can have lethal adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use can’t reliably predict the CRS in patients. A predictive marker for identifying patients at risk for developing CRS upfront would improve the safety of immune-oncology drug development. Methods: We have developed a rapid, sensitive and reproducible in vivo humanized mouse model for quantitating CRS. The NSG mouse and its derivatives are engrafted with human PBMCs. On day 6 we induced cytokines release with pembrolizumab, avelumab, atezolizumab, ipilimumab, anti-CD28, ATG and OKT3 in single dose; as well as combination treatments involving pembrolizumab, lenalidomide, ATG and anti-CD28. Furthermore, we compared our method versus the in vitro PBMC assay. The cytokine levels were also compared to the dose response. Results: There are about 10-15% CD45+ human cells on day 5 of engraftment; and among of them, there were approximately 70% CD3 T cells and 25% CD56 NK cells. All tested cytokines, human IFN-γ, IL-2, IL-4, IL-6, IL-10 and TNF were upregulated after 2 and 6 hours of OKT3, ATG, anti-CD28, pembrolizumab, avelumab and atezolizumab drug treatment. Mouse’s rectal temperatures dropped from 37-38 °C to about 36 °C at 6 hours’ time point in the treated groups. There is various cytokines release levels, low to high response in different donors with anti-CD28 treatment. All donors showed high response to OKT3. The cytokine release levels were consistent with a dose response or variable PBMC engraftment. The cytokine levels were also higher in some drug combination studies such as pembrolizumab combined with lenalidomide or ATG; anti-CD28 combined with ATG. Our in vivo method was able to determine CRS missed in the in vitro testing method. Conclusions: We have developed a rapid, sensitive and reproducible novel in vivo PBMC humanized mouse model that is able to differentiate human PBMC donors based on individual safety response to single agent and combination therapeutics of immune checkpoint inhibitors and possibly CAR-T therapy. This assay could be employed in future drug development.

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Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

Drug Metabolism and Disposition ◽

10.1124/dmd.114.061812 ◽

2014 ◽

Vol 43 (2) ◽

pp. 208-216 ◽

Cited By ~ 12

Author(s):

Zhihua Liu ◽

Lei Li ◽

Hong Wu ◽

Jing Hu ◽

Jun Ma ◽

...

Keyword(s):

Mouse Model ◽

Nicotine Metabolism ◽

Humanized Mouse ◽

Humanized Mouse Model

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Targeting Lysyl oxidase-like 2 in Idiopathic Pulmonary Fibrosis

10.1101/813907 ◽

2019 ◽

Cited By ~ 1

Author(s):

Milena S. Espindola ◽

David M Habiel ◽

Ana Lucia Coelho ◽

Amanda Mikels-Vigdal ◽

Cory M. Hogaboam

Keyword(s):

Pulmonary Fibrosis ◽

Mouse Model ◽

Lysyl Oxidase ◽

Lung Fibroblasts ◽

Normal Lung ◽

Dependent Manner ◽

Humanized Mouse ◽

Humanized Mouse Model

AbstractThe composition of extracellular matrix (ECM) is altered during pathologic scarring in damaged organs including the lung. One major change in the ECM involves the cross-linking of collagen, which promotes fibroblast to myofibroblast differentiation.ObjectiveWe examined the role of lysyl oxidase (LOX)-like 2 in lung fibroblasts cultured from normal or IPF lung samples and in a humanized mouse model of IPF using a monoclonal antibody (Simtuzumab).Research Design and MethodsPrimary lung fibroblasts from normal donor lungs and IPF lung explants were examined for expression of LOXL2. Targeting LOXL2 with Simtuzumab on normal and IPF fibroblasts was examined both in vitro and in vivo for synthetic, functional, and profibrotic properties.ResultsLOXL2 was increased at transcript and protein level in IPF compared with normal lung samples. In a dose-dependent manner, Simtuzumab enhanced differentiation of fibroblasts into myofibroblasts. Inhibition of LOXL2 also enhanced fibroblast invasion and accelerated the outgrowth of fibroblasts from dissociated human lung cell preparations. Finally, preventative or delayed delivery of Simtuzumab enhanced lung fibrosis in a humanized mouse model of pulmonary fibrosis.ConclusionConsistent with its failure in a Phase 2 clinical trial, Simtuzumab exhibited no therapeutic efficacy in translational in vitro and in vivo assays.

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