Human FcRn Transgenic Mice for Pharmacokinetic Evaluation of Therapeutic Antibodies

2016 ◽  
pp. 103-114 ◽  
Author(s):  
Derry C. Roopenian ◽  
Gregory J. Christianson ◽  
Gabriele Proetzel ◽  
Thomas J. Sproule
Keyword(s):  
Transgenic Mice ◽  
Therapeutic Antibodies ◽  
Pharmacokinetic Evaluation

Trastuzumab-reactive antibodies (TR-abs) in serum and trastuzumab (Tzb) benefit prediction in patients with HER2-overexpressing breast cancer.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 77-77 ◽  
Author(s):  
Paula Raffin Pohlmann ◽  
Todd W. Miller ◽  
David L Blum ◽  
Dipti Pareh ◽  
Heping Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Transgenic Mice ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Breast Cancer Cell Lines ◽  
Therapeutic Antibodies ◽  
Stage Iv Breast Cancer ◽  
Pharmacologically Active

77 Background: Trastuzumab (Tzb) is a humanized monoclonal antibody (MAb) approved for treatment of HER2-overexpressing breast cancer. Unfortunately not all patients benefit from it and lack of response cannot be predicted. We detected TR-abs in serum of mice and patients treated with Tzb. We hypothesized that TR-abs would associate with response to therapy. Methods: Direct/competition ELISA, dot blot, and mass spectrometry were used to detect and characterize TR-abs in sera from Tzb treated FVBMMTV/HER2transgenic mice, from hybridoma MAbs stemming from transgenic mice responding favorably to Tzb (992-18 mMAb), and in sera of 22 patients with metastatic breast cancer enrolled in a phase I clinical trial. WST-1 viability assay was used to assess biological activity of 992-18 on SKBR3 or BT474 human breast cancer cell lines. Results: From 12 mice bearing HER2-overexpressing tumors and treated with Tzb, 5 responded to therapy and 7 exhibited progressive disease (PD). All 5 responders had elevated TR-abs, whereas TR-abs were low/undetectable with PD (p=0.002; Mann-Whitney two-tailed). This was confirmed in a second cohort of 16 mice, in which TR-abs were undetectable prior to treatment, but gradually detected with Tzb therapy and tumor regression. TR-MAb 992-18 directly targeted also SKBR3 and BT474 in cell-based ELISAs and immunofluorescence assays. Treatment with 992-18 reduced BT474 and SKBR3 cell viability in comparison to isotype-matched control Ab (p<0.0001). In sera from patients with metastatic breast cancer, higher concentrations of TR-abs were significantly associated with lower risk of disease progression (p=0.023, Cox regression, univariate analysis). Conclusions: Low serum TR-abs are associated with poor response to Tzb in mice and with shorter progression free survival in women with HER2 overexpressing stage IV breast cancer. In addition, TR-abs (e.g. 992-18) produced in response to therapy may be pharmacologically active. Results support prospective evaluation of patients undergoing treatment with therapeutic antibodies to determine if this non-invasive immunoassay detecting anti-therapeutic antibodies would predict benefit to therapy.

Quantitative Microscopic Comparison of the Organization of the Lung in Transgenic Mice Expressing Transforming Growth Factor-α (TGF-α)

1996 ◽  
Vol 54 ◽  
pp. 14-15
Author(s):  
C. G. Plopper ◽  
C. Helton ◽  
A. J. Weir ◽  
J. A. Whitsett ◽  
T. R. Korfhagen
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transgenic Mice ◽  
Blood Vessels ◽  
Lung Parenchyma ◽  
Lung Maturation ◽  
Alveolar Air ◽  
Parenchymal Tissue ◽  
Air Space ◽  
Conducting Airways

A wide variety of growth factors are thought to be involved in the regulation of pre- and postnatal lung maturation, including factors which bind to the epidermal growth factor receptor. Marked pulmonary fibrosis and enlarged alveolar air spaces have been observed in lungs of transgenic mice expressing human TGF-α under control of the 3.7 KB human SP-C promoter. To test whether TGF-α alters lung morphogenesis and cellular differentiation, we examined morphometrically the lungs of adult (6-10 months) mice derived from line 28, which expresses the highest level of human TGF-α transcripts among transgenic lines. Total volume of lungs (LV) fixed by airway infusion at standard pressure was similar in transgenics and aged-matched non-transgenic mice (Fig. 1). Intrapulmonary bronchi and bronchioles made up a smaller percentage of LV in transgenics than in non-transgenics (Fig. 2). Pulmonary arteries and pulmonary veins were a smaller percentage of LV in transgenic mice than in non-transgenics (Fig. 3). Lung parenchyma (lung tissue free of large vessels and conducting airways) occupied a larger percentage of LV in transgenics than in non-transgenics (Fig. 4). The number of generations of branching in conducting airways was significantly reduced in transgenics as compared to non-transgenic mice. Alveolar air space size, as measured by mean linear intercept, was almost twice as large in transgenic mice as in non-transgenics, especially when different zones within the lung were compared (Fig. 5). Alveolar air space occupied a larger percentage of the lung parenchyma in transgenic mice than in non-transgenic mice (Fig. 6). Collagen abundance was estimated in histological sections as picro-Sirius red positive material by previously-published methods. In intrapulmonary conducting airways, collagen was 4.8% of the wall in transgenics and 4.5% of the wall in non-transgenic mice. Since airways represented a smaller percentage of the lung in transgenics, the volume of interstitial collagen associated with airway wall was significantly less. In intrapulmonary blood vessels, collagen was 8.9% of the wall in transgenics and 0.7% of the wall in non-transgenics. Since blood vessels were a smaller percentage of the lungs in transgenics, the volume of collagen associated with the walls of blood vessels was five times greater. In the lung parenchyma, collagen was 51.5% of the tissue volume in transgenics and 21.2% in non-transgenics. Since parenchyma was a larger percentage of lung volume in transgenics, but the parenchymal tissue was a smaller percent of the volume, the volume of collagen associated with parenchymal tissue was only slightly greater. We conclude that overexpression of TGF-α during lung maturation alters many aspects of lung development, including branching morphogenesis of the airways and vessels and alveolarization in the parenchyma. Further, the increases in visible collagen previously associated with pulmonary fibrosis due to the overexpression of TGF-α are a result of actual increases in amounts of collagen and in a redistribution of collagen within compartments which results from morphogenetic changes. These morphogenetic changes vary by lung compartment. Supported by HL20748, ES06700 and the Cystic Fibrosis Foundation.

Eleveted serum gastrin level cannot maintain basal and stimulated gastric acid secretion in histamine deficient transgenic mice

2001 ◽  
Vol 120 (5) ◽  
pp. A180-A180
Author(s):  
B HUNYADY ◽  
A ZOLYOMI ◽  
J CZIMMER ◽  
G MOZSIK ◽  
E BUZAS ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Serum Gastrin ◽  
Gastrin Level ◽  
Serum Gastrin Level
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