Identification of Cell Autonomous and Non-Cell Autonomous Functions of Heparan Glycosaminoglycan Chains by Creating Chimeric Mouse

SummaryBackground BI 836826 is a chimeric mouse–human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.

Download Full-text

Chimeric Mouse With Humanized Liver Is an Appropriate Animal Model to Investigate Mode of Action for Porphyria-Mediated Hepatocytotoxicity

Toxicologic Pathology ◽

10.1177/01926233211027474 ◽

2021 ◽

pp. 019262332110274

Author(s):

Ayumi Eguchi ◽

Satoki Fukunaga ◽

Keiko Ogata ◽

Masahiko Kushida ◽

Hiroyuki Asano ◽

...

Keyword(s):

Experimental Model ◽

Mode Of Action ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Human Hepatocytes ◽

Chimeric Mouse ◽

Hepatocellular Injury ◽

Hepatocyte Necrosis ◽

Key Events

Porphyrinogenic compounds are known to induce porphyria-mediated hepatocellular injury and subsequent regenerative proliferation in rodents, ultimately leading to hepatocellular tumor induction. However, an appropriate in vivo experimental model to evaluate an effect of porphyrinogenic compounds on human liver has not been fully established. Recently, the chimeric mouse with humanized liver (PXB mice) became widely used as a humanized model in which human hepatocytes are transplanted. In the present study, we examined the utility of PXB mice as an in vivo experimental model to evaluate the key events of the porphyria-mediated cytotoxicity mode of action (MOA) in humans. The treatment of PXB mice with 5-aminolevulinic acid, a representative porphyrinogenic compound, for 28 days caused protoporphyrin IX accumulation, followed by hepatocyte necrosis, increased mitosis, and an increase in replicative DNA synthesis in human hepatocytes, indicative of cellular injury and regenerative proliferation, similar to findings in patients with porphyria or experimental porphyria models and corresponding to the key events of the MOA for porphyria-mediated hepatocellular carcinogenesis. We conclude that the PXB mouse is a useful model to evaluate the key events of the porphyria-mediated cytotoxicity MOA in humans and suggest the utility of PXB mice for clarifying the human relevancy of findings in mice.

Download Full-text

Maintenance Therapy in Crohn's Disease

Canadian Journal of Gastroenterology ◽

10.1155/2000/480782 ◽

2000 ◽

Vol 14 (suppl c) ◽

pp. 23C-28C ◽

Cited By ~ 9

Author(s):

Hillary Steinhart

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Maintenance Therapy ◽

Immunosuppressive Agents ◽

Human Antibody ◽

Chimeric Mouse ◽

Wide Range ◽

Systemic Glucocorticoids ◽

Necrosis Factor

Symptoms of active Crohn’s disease may respond to one or more of a number of classes of drug therapies. These include systemic glucocorticoids, budesonide, sulphasalazine, mesalazine (5-aminosalicylates), immunosuppressive agents and antibiotics. More recently, a chimeric mouse-human antibody to tumour necrosis factor (infliximab) has been shown to induce clinical remission and endoscopic improvement in patients with moderately active Crohn’s disease refractory to other therapies. Despite this wide range of existing therapies and the potential of emerging biological therapies, recurrent Crohn’s disease continues to be a major impediment to the fulfilment of a normal lifestyle and optimal quality of life for patients with Crohn’s disease. Many drugs known to be effective for the treatment of active disease have been tried as maintenance therapy to prevent disease relapse or recurrence following medical or surgical therapy. The available evidence suggests that most of these drugs are not as useful in maintaining remission as they are in inducing it. Systemic glucocorticoids, budesonide, mesalazine (5-aminosalicylates), sulphasalazine and antibiotics are all associated with either marginal therapeutic gain in the setting of maintenance therapy or unacceptable long term toxicity. The immunosuppressive agents azathioprine, 6-mercaptopurine and methotrexate have been shown to have a beneficial effect in maintaining remission and may be helpful as steroid-sparing agents. Repeated infusions of antitumour necrosis factor antibody maintain the improvements observed after one or two initial infusions. The relative long term safety, efficacy and cost effectiveness of the various choices of maintenance therapy remain to be determined.

Download Full-text

Arachidonic acid-regulated calcium signaling in T cells from patients with rheumatoid arthritis promotes synovial inflammation

Nature Communications ◽

10.1038/s41467-021-21242-z ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Zhongde Ye ◽

Yi Shen ◽

Ke Jin ◽

Jingtao Qiu ◽

Bin Hu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Arachidonic Acid ◽

Lupus Erythematosus ◽

Calcium Influx ◽

Cell Receptor ◽

Synovial Inflammation ◽

Chimeric Mouse ◽

T Cell Receptor Signaling ◽

Chimeric Mouse Model

AbstractRheumatoid arthritis (RA) and psoriatic arthritis (PsA) are two distinct autoimmune diseases that manifest with chronic synovial inflammation. Here, we show that CD4+ T cells from patients with RA and PsA have increased expression of the pore-forming calcium channel component ORAI3, thereby increasing the activity of the arachidonic acid-regulated calcium-selective (ARC) channel and making T cells sensitive to arachidonic acid. A similar increase does not occur in T cells from patients with systemic lupus erythematosus. Increased ORAI3 transcription in RA and PsA T cells is caused by reduced IKAROS expression, a transcriptional repressor of the ORAI3 promoter. Stimulation of the ARC channel with arachidonic acid induces not only a calcium influx, but also the phosphorylation of components of the T cell receptor signaling cascade. In a human synovium chimeric mouse model, silencing ORAI3 expression in adoptively transferred T cells from patients with RA attenuates tissue inflammation, while adoptive transfer of T cells from healthy individuals with reduced expression of IKAROS induces synovitis. We propose that increased ARC activity due to reduced IKAROS expression makes T cells more responsive and contributes to chronic inflammation in RA and PsA.

Download Full-text

Functional Analysis of Human Hepatocytes Isolated From Chimeric Mouse Liver

Transplantation Proceedings ◽

10.1016/j.transproceed.2018.06.035 ◽

2018 ◽

Vol 50 (10) ◽

pp. 3858-3862 ◽

Cited By ~ 1

Author(s):

N. Harimoto ◽

H. Nakagawara ◽

K. Shirabe ◽

T. Yoshizumi ◽

S. Itoh ◽

...

Keyword(s):

Functional Analysis ◽

Mouse Liver ◽

Human Hepatocytes ◽

Chimeric Mouse

Download Full-text

Distribution of Bone Marrow-Derived Cells in the Fracture Callus during Plate Fixation in a Green Fluorescent Protein-Chimeric Mouse Model

Experimental Animals ◽

10.1538/expanim.60.455 ◽

2011 ◽

Vol 60 (5) ◽

pp. 455-462 ◽

Cited By ~ 16

Author(s):

Masaki UENO ◽

Kentaro UCHIDA ◽

Masashi TAKASO ◽

Hiroaki MINEHARA ◽

Kaori SUTO ◽

...

Keyword(s):

Bone Marrow ◽

Green Fluorescent Protein ◽

Mouse Model ◽

Fluorescent Protein ◽

Plate Fixation ◽

Chimeric Mouse ◽

Fracture Callus ◽

Bone Marrow Derived Cells ◽

Chimeric Mouse Model ◽

Green Fluorescent

Download Full-text

Analyzing Glucose Phosphate Isomerase Isozymes in Chimeric Mouse Tissues by Electrophoresis

Cold Spring Harbor Protocols ◽

10.1101/pdb.prot4813 ◽

2008 ◽

Vol 2008 (10) ◽

pp. pdb.prot4813-pdb.prot4813

Author(s):

A. Nagy ◽

M. Gertsenstein ◽

K. Vintersten ◽

R. Behringer

Keyword(s):

Chimeric Mouse ◽

Glucose Phosphate Isomerase ◽

Glucose Phosphate ◽

Mouse Tissues

Download Full-text

Human liver chimeric mouse model based on diphtheria toxin-induced liver injury

World Journal of Gastroenterology ◽

10.3748/wjg.v23.i27.4935 ◽

2017 ◽

Vol 23 (27) ◽

pp. 4935

Author(s):

Xiao-Nan Ren ◽

Rong-Rong Ren ◽

Hua Yang ◽

Bo-Yin Qin ◽

Xiu-Hua Peng ◽

...

Keyword(s):

Liver Injury ◽

Mouse Model ◽

Diphtheria Toxin ◽

Human Liver ◽

Chimeric Mouse ◽

Model Based ◽

Chimeric Mouse Model

Download Full-text

Generation and Activity Evaluation of a Mouse-Human Immunoglobulin G1 Chimeric Antibody to Histoplasma capsulatum HSP60

10.20944/preprints202104.0101.v1 ◽

2021 ◽

Author(s):

Ágata Nogueira D'Áurea Moura ◽

Scott J. Garforth ◽

Leandro Buffoni Roque da Silva ◽

Darien Woodley ◽

Filipe Vieira Barbalho ◽

...

Keyword(s):

Monoclonal Antibody ◽

Histoplasma Capsulatum ◽

Physiological Stress ◽

Human Monoclonal Antibody ◽

Current Treatment ◽

Chimeric Antibody ◽

Human Antibody ◽

Chimeric Mouse ◽

Dimorphic Fungi

Heat shock proteins (Hsps) are highly conserved molecules that are constitutively expressed and upregulated in response to physiological stress conditions. These immunogenic chaperones can have essential functions in fungi, particularly in dimorphic pathogens. Histoplasma capsulatum and Paracoccidioides species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively, which are systemic mycoses with significant rates of morbidity and mortality. Current treatment consists of long-term antifungal agents, and there is an urgent need for new therapeutic approaches with higher efficacy, lower toxicity, better biodistribution and improved selectivity. We engineered an immunoglobulin G1 (IgG1) isotype chimeric mouse-human monoclonal antibody, titled ch-MAb 4E12, from the parental IgG2a MAb 4E12, a monoclonal antibody to H. capsulatum Hsp60 that is protective in experimental histoplasmosis and paracoccidioidomycosis models elicited by H. capsulatum var. capsulatum and Paracoccidioides lutzii, respectively. The ch-MAb 4E12 increased phagolysosomal fusion and enhanced the yeasts uptake by PMA differentiated human THP1 macrophage cells in vitro. At low concentrations, the chimeric antibody significantly reduced the pulmonary and splenic fungal burden compared to an irrelevant antibody or no treatment. These results are the first to show that a chimeric mouse-human antibody can modify infection caused by dimorphic fungi.

Download Full-text