scholarly journals Preclinical platform for long-term evaluation of immuno-oncology drugs using hCD34+ humanized mouse model

2020 ◽  
Vol 8 (2) ◽  
pp. e001513
Author(s):  
Nahee Park ◽  
Kamal Pandey ◽  
Sei Kyung Chang ◽  
Ah-Young Kwon ◽  
Young Bin Cho ◽  
...  
Keyword(s):  
Mouse Model ◽  
Humanized Mice ◽  
Preclinical Models ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Durable Response ◽  
Term Efficacy ◽  
Nsg Mice ◽  
Oncology Research

BackgroundWell-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.MethodsHumanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.ResultsBusulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.ConclusionsOur CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.

scholarly journals Long-Term Faithful Recapitulation of Transglutaminase 1–Deficient Lamellar Ichthyosis in a Skin-Humanized Mouse Model, and Insights from Proteomic Studies

2012 ◽  
Vol 132 (7) ◽  
pp. 1918-1921 ◽  
Author(s):  
Karin Aufenvenne ◽  
Robert H. Rice ◽  
Ingrid Hausser ◽  
Vinzenz Oji ◽  
Hans Christian Hennies ◽  
...  
Keyword(s):  
Mouse Model ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Lamellar Ichthyosis ◽  
Transglutaminase 1

scholarly journals A functional DC cross talk promotes human ILC homeostasis in humanized mice

2017 ◽  
Vol 1 (10) ◽  
pp. 601-614 ◽  
Author(s):  
Silvia Lopez-Lastra ◽  
Guillemette Masse-Ranson ◽  
Oriane Fiquet ◽  
Sylvie Darche ◽  
Nicolas Serafini ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cross Talk ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Key Points

Key Points A novel humanized mouse model to study human ILC biology. Human DC cross talk with ILCs in vivo.

scholarly journals 14 Novel CD3 epsilon humanized N-terminal epitope model for assessment of efficacy of T-cell engagers

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A14-A14
Author(s):  
Gaëlle Martin ◽  
Fabiane Sônego ◽  
Audrey Beringer ◽  
Chloé Beuraud ◽  
Yacine Cherifi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
Humanized Mice ◽  
Dependent Manner ◽  
Salt Bridges ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Concentration Dependent Manner

BackgroundT-cell engagers have proved to be a promising therapeutic strategy in immunotherapy, for redirecting T cells activity against tumor cells. To facilitate the preclinical assessment of novel T-cell engagers and their translatability, we have developed an immunocompetent CD3 epsilon N-terminal epitope humanized mouse model.MethodsThis model was developed to express the human epitope of the CD3 epsilon chain, which is recognized by approximately 70% of the T-cell engagers (clone SP34). The rest of the extracellular domain was kept from mouse origin to preserve the amino acids involved in the interaction with CD3 gamma and delta. Similarly, the transmembrane domains and the intracellular domains where kept murine to enable salt bridges interaction, interaction with the CD3 zeta and the signaling into mouse cells.ResultsT cells from CD3 epsilon epitope humanized mice are found in comparable frequency in spleen, blood and bone marrow from WT mice. B cells, monocytes, dendritic cells and NK frequencies are also similar to the frequencies of these cell types in WT mice, suggesting that the humanization of the epitope of CD3 epsilon did not alter the immune cells distribution in these mice. Activation of T cells with antibodies targeting human CD3 (clone SP34) induced CD4 and CD8 T cell proliferation, as well as production of IL-2 and IFN-gamma. The CD3 functionality was demonstrated in vitro by the ability of B cells to produce IgM upon activation of T cells, suggesting a proper cooperation between T and B cells. Additionally, a first class of T-cell engagers targeting both human CD3 and a tumoral antigen, induced tumor cell lysis of MC38-Ag in a concentration-dependent manner. A second class of T cell engagers, also targeting CD3 and a tumoral antigen, showed an anti-tumor effect in vivo, and this effect was also shown to be dose-dependent.ConclusionsThese data suggest that the CD3 epsilon N-terminal epitope humanized mouse model enables the assessment of efficacy and mechanism of action of T-cell engagers.This model is currently being intercrossed with immunostimulatory humanized mouse models to provide new opportunities for assessment of bi-specific antibodies targeting the CD3 and immunostimulatory molecules. This model is the first generation of a broader program aiming at developping a Pan CD3 humanized model, where the gamma, delta and epsilon chains of the CD3 complex will be humanized. The Pan CD3 humanized mice are currently being investigated for immune responses and would provide a broader tool for assessment of T-cell engagers.

scholarly journals A novel humanized mouse model with significant improvement of class-switched, antigen-specific antibody production

Blood ◽  
2017 ◽  
Vol 129 (8) ◽  
pp. 959-969 ◽  
Author(s):  
Hua Yu ◽  
Chiara Borsotti ◽  
Jean-Nicolas Schickel ◽  
Shu Zhu ◽  
Till Strowig ◽  
...  
Keyword(s):  
Mouse Model ◽  
High Specificity ◽  
Memory B Cells ◽  
Humanized Mice ◽  
Antibody Repertoire ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Cell Engraftment ◽  
Key Points ◽  
Specific Antibody Production

Key Points Human IL-6 improves T-cell engraftment and serum IgG production in humanized mice. IgG-switched memory B cells in IL-6 knock-in mice displayed a diverse antibody repertoire and high specificity against immunized antigen.

scholarly journals Nanoencapsulated rituximab mediates superior cellular immunity against metastatic B-cell lymphoma in a complement competent humanized mouse model

2021 ◽  
Vol 9 (2) ◽  
pp. e001524
Author(s):  
Jing Wen ◽  
Lan Wang ◽  
Jie Ren ◽  
Emiko Kranz ◽  
Shilin Chen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cancer Therapeutics ◽  
B Cell Lymphoma ◽  
Cancer Targeting ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Nsg Mice ◽  
Complement Dependent Cytotoxicity ◽  
Burkitt Lymphoma Cell Line ◽  
Cellular Immune

BackgroundDespite the numerous applications of monoclonal antibodies (mAbs) in cancer therapeutics, animal models available to test the therapeutic efficacy of new mAbs are limited. NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice are one of the most highly immunodeficient strains and are universally used as a model for testing cancer-targeting mAbs. However, this strain lacks several factors necessary to fully support antibody-mediated effector functions—including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity (CDC)—due to the absence of immune cells as well as a mutation in the Hc gene, which is needed for a functional complement system.MethodsWe have developed a humanized mouse model using a novel NSG strain, NOD.Cg−Hc1Prkdcscid Il2rgtm1Wjl/SzJ (NSG−Hc1), which contains the corrected mutation in the Hc gene to support CDC in addition to other mechanisms endowed by humanization. With this model, we reevaluated the anticancer efficacies of nanoencapsulated rituximab after xenograft of the human Burkitt lymphoma cell line 2F7-BR44.ResultsAs expected, xenografted humanized NSG−Hc1 mice supported superior lymphoma clearance of native rituximab compared with the parental NSG strain. Nanoencapsulated rituximab with CXCL13 conjugation as a targeting ligand for lymphomas further enhanced antilymphoma activity in NSG−Hc1 mice and, more importantly, mediated antilymphoma cellular responses.ConclusionsThese results indicate that NSG−Hc1 mice can serve as a feasible model for both studying antitumor treatment using cancer targeting as well as understanding induction mechanisms of antitumor cellular immune response.

scholarly journals Experimental adaptive evolution of SIVcpz to pandemic HIV-1 using a humanized mouse model

2017 ◽  
pp. JVI.01905-17 ◽  
Author(s):  
Kei Sato ◽  
Naoko Misawa ◽  
Junko S Takeuchi ◽  
Tomoko Kobayashi ◽  
Taisuke Izumi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Causative Agent ◽  
Humanized Mice ◽  
Humanized Mouse ◽  
Gain Of Function ◽  
Humanized Mouse Model ◽  
Hematopoietic Stem ◽  
Human Virus ◽  
The Cross ◽  
Hiv 1

HIV-1, the causative agent of AIDS, is originated from SIVcpz, the chimpanzee precursor of the human virus, approximately 100 years ago. This indicates that HIV-1 has emerged through the cross-species transmission of SIVcpz from chimpanzees to humans. However, it remains unclear how SIVcpz has evolved into pandemic HIV-1 in humans. To address this question, we inoculated three SIVcpz (MB897, EK505, and MT145), four pandemic HIV-1 (NL4-3, NLCSFV3, JRCSF and AD8) and 2 non-pandemic HIV-1 (YBF30 and DJO0131) strains. Humanized mice infected with SIVcpz strain MB897, a virus phylogenetically similar to pandemic HIV-1, exhibited a comparable peak viral load to that of mice infected with pandemic HIV-1, while peak viral loads of mice infected with SIVcpz strains EK505 or MT145 as well as non-pandemic HIV-1 strains were significantly lower. These results suggest that SIVcpz strain MB897 is pre-adapted to humans when compared to the other SIVcpz strains. Moreover, viral RNA sequencing of MB897-infected humanized mice identified a nonsynonymous mutation inenv, G413R substitution in gp120. The infectivity of the gp120 G413R mutant of MB897 was significantly higher than that of parental MB897. Furthermore, we demonstrated that the gp120 G413R mutant of MB897 augments the capacity for viral replication in bothin vitrocell cultures and humanized mice. Taken together, this is the first experimental investigation to use an animal model to demonstrate a gain-of-function evolution of SIVcpz into pandemic HIV-1.ImportanceFrom the mid-20th century, humans are exposed to the menace of viral infectious diseases such as SARS coronavirus, Ebola virus and Zika virus. These outbreaks of emerging/re-emerging viruses can be triggered by cross-species viral transmission from wild animals to humans or zoonoses. HIV-1, the causative agent of AIDS, was emerged by the cross-species transmission of SIVcpz, the HIV-1 precursor in chimpanzee, around 100 years ago. However, the process by which SIVcpz evolved to become HIV-1 in humans remains unclear. By using a hematopoietic stem cell-transplanted humanized mouse model, here we experimentally recapitulate the evolutionary process of SIVcpz to become HIV-1. We provide evidence suggesting that a strain of SIVcpz, MB897, has pre-adapted to infect humans comparing to other SIVcpz strains. We further demonstrate a gain-of-function evolution of SIVcpz in infected humanized mice. Our study reveals that pandemic HIV-1 has emerged through at least two steps: preadaptation and subsequent gain-of-function mutations.

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