ErbB Receptor Activation, Cell Morphology Changes, and Apoptosis Induced by Anti-Her2 Monoclonal Antibodies

1996 ◽  
Vol 226 (1) ◽  
pp. 59-69 ◽  
Author(s):  
Yoshiko Kita ◽  
Julia Tseng ◽  
Thomas Horan ◽  
Jie Wen ◽  
John Philo ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Morphology ◽  
Receptor Activation ◽  
Erbb Receptor ◽  
Morphology Changes

scholarly journals erbB-1 and erbB-4 Receptors Act in Concert to Facilitate Female Sexual Development and Mature Reproductive Function

Endocrinology ◽  
2005 ◽  
Vol 146 (3) ◽  
pp. 1465-1472 ◽  
Author(s):  
Vincent Prevot ◽  
Alejandro Lomniczi ◽  
Gabriel Corfas ◽  
Sergio R. Ojeda
Keyword(s):  
Glial Cells ◽  
Sexual Development ◽  
Double Mutant ◽  
Reproductive Function ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Reproductive Capacity ◽  
Erbb Receptor ◽  
Signaling Systems ◽  
Lhrh Release

Glial erbB-1 and erbB-4 receptors are key components of the process by which neuroendocrine glial cells control LHRH secretion and the onset of female puberty. We now provide evidence that these two signaling systems work in a coordinated fashion to control reproductive function. To generate animals carrying functionally impaired erbB-1 and erbB-4 receptors, we crossed Waved 2 (Wa-2+/+) mice harboring a point mutation of the erbB-1 receptor with mice expressing a dominant-negative erbB-4 receptor in astrocytes. In comparison to single-deficient mice, double-mutant animals exhibited a further delay in the onset of puberty and a strikingly diminished adult reproductive capacity. Ligand-dependent erbB receptor phosphorylation and erbB-mediated MAPK (ERK 1/2) phosphorylation were impaired in mutant astrocytes. Wa-2+/+ or double-mutant astrocytes failed to respond to TGFα with production of prostaglandin E2, one of the factors mediating the stimulatory effect of astroglial erbB receptor activation on LHRH release. Medium conditioned by Wa-2+/+ or double-mutant astrocytes treated with TGFα failed to stimulate LHRH release from GT1–7 cells. The LH response to ovariectomy was significantly attenuated in mutant mice in comparison with wild-type controls. Although the Wa-2 mutation affects all cells bearing erbB-1 receptors, these results suggest that a major defect underlying the reproductive defects of animals with impaired erbB signaling is a decreased ability of glial cells to stimulate LHRH release. Thus, a coordinated involvement of erbB-1 and erbB-4 signaling systems is required for the normalcy of sexual development and the maintenance of mature female reproductive function.

Modulation of the biological activity of thyrotrophin by anti-human thyrotrophin monoclonal antibodies

1990 ◽  
Vol 126 (2) ◽  
pp. 333-340 ◽  
Author(s):  
S. R. Page ◽  
A. H. Taylor ◽  
W. Driscoll ◽  
M. Baines ◽  
R. Thorpe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Biological Activity ◽  
Monoclonal Antibodies ◽  
Cyclic Amp ◽  
Receptor Activation ◽  
Camp Production ◽  
Dose Dependent ◽  
Bovine Tsh

ABSTRACT The mechanism by which monoclonal antibodies enhance the biological activity of a number of hormones is poorly understood. One such antibody (GC73), which binds to human but not bovine TSH, enhances the bioactivity of human TSH in vivo. We have investigated whether GC73 enhancement of TSH bioactivity involves potentiation of hormone-receptor activation assessed by the cyclic AMP (cAMP) responses of both primary human thyrocyte cultures and a TSH-responsive human thyrocyte cell line (SGHTL-45). GC73 had no effect on basal cAMP production. In contrast to its enhancement of the bioactivity of human TSH in vivo, it markedly inhibited the cAMP response to 1 and 10 mU human TSH/ml in primary thyrocytes. This effect was dose-dependent with neutralization of the bioactivity of TSH occurring at 2 mg GC73/ml. GC73 had no effect on the bioactivity of bovine TSH. In contrast, a second anti-TSH monoclonal antibody (TC12), which binds to both human and bovine TSH, inhibited the bioactivity of both species of TSH. Similar results were obtained using SGHTL-45 cells, although the peak concentrations of cAMP were lower. We conclude that binding of GC73 to human TSH resulted in inhibition rather than enhancement of the in-vitro biological activity of human TSH. We suggest that GC73 enhancement of human TSH bioactivity seen in vivo does not result from a mechanism involving potentiation of receptor activation by human TSH. Journal of Endocrinology (1990) 126, 333–340

scholarly journals Anti-EphA2 Antibodies with Distinct In Vitro Properties Have Equal In Vivo Efficacy in Pancreatic Cancer

2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Helenia Ansuini ◽  
Annalisa Meola ◽  
Zeynep Gunes ◽  
Valentina Paradisi ◽  
Monica Pezzanera ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibodies ◽  
Therapeutic Potential ◽  
Tumor Cell Line ◽  
Immunohistochemical Analysis ◽  
Receptor Activation ◽  
Rapid Identification ◽  
Antibody Treatment

The EphA2 receptor tyrosine kinase is overexpressed in a variety of human epithelial cancers and is a determinant of malignant cellular behavior in pancreatic adenocarcinoma cells. Moreover, it is expressed in tumor endothelium and its activation promotes angiogenesis. To better clarify the therapeutic potential of monoclonal antibodies (mAbs) directed to the EphA2 receptor, we generated a large number of mAbs by differential screening of phage-Ab libraries by oligonucleotide microarray technology and implemented a strategy for the rapid identification of antibodies with the desired properties. We selected two high-affinity and highly specific EphA2 monoclonal antibodies with different in vitro properties on the human pancreatic tumor cell line MiaPaCa2. One is a potent EphA2-agonistic antibody, IgG25, that promotes receptor endocytosis and subsequent degradation, and the second is a ligand antagonist, IgG28, that blocks the binding to ephrin A1 and is cross-reactive with the mouse EphA2 receptor. We measured the effect of antibody treatment on the growth of MiaPaCa2 cells orthotopically transplanted in nude mice. Both IgG25 and IgG28 had strong antitumor and antimetastatic efficacy. In vivo treatment with IgG25 determined the reduction of the EphA2 protein levels in the tumor and the phosphorylation of FAK on Tyr576 while administration of IgG28 caused a decrease in tumor vascularization as measured by immunohistochemical analysis of CD31 in tumor sections. These data show that in a pancreatic cancer model comparable therapeutic efficacy is obtained either by promoting receptor degradation or by blocking receptor activation.

Behavioral response and cell morphology changes of Caenorhabditis elegans under high power millimeter wave irradiation

2010 ◽  
Vol 22 (12) ◽  
pp. 2949-2954
Author(s):  
任长虹 Ren Changhong ◽  
袁广江 Yuan Guangjiang ◽  
高艳 Gao Yan ◽  
吴永红 Wu Yonghong ◽  
徐志伟 Xu Zhiwei ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Millimeter Wave ◽  
Cell Morphology ◽  
High Power ◽  
Behavioral Response ◽  
Morphology Changes

Integrated analysis of ERBB receptor activation and downstream signaling with EXTassays

2010 ◽  
Vol 27 ◽  
pp. S37
Author(s):  
A. Botvinnik ◽  
S.P. Wichert ◽  
T.M. Fischer ◽  
M.J. Rossner
Keyword(s):  
Receptor Activation ◽  
Integrated Analysis ◽  
Erbb Receptor ◽  
Downstream Signaling

scholarly journals Combined method for simultaneous morphology, immunophenotype and karyotype (MAC) in leukemias

1997 ◽  
Vol 115 (1) ◽  
pp. 1336-1342 ◽  
Author(s):  
Maria de Lourdes Lopes Ferrari Chauffaille ◽  
Vicente Coutinho ◽  
Mihoko Yamamoto ◽  
José Kerbauy
Keyword(s):  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Acute Leukemia ◽  
Cell Morphology ◽  
Direct Method ◽  
Blast Crisis ◽  
Leukemic Cell ◽  
Combined Method ◽  
Gm Csf ◽  
Simultaneous Identification

In the present study, a combined method (CM) for attaining simultaneous identification of leukemic cell morphology, karyotype and immunophenotype has been evaluated in 21 patients with acute leukemia and 1 with CML in blast crisis were studied for morphology, citochemistry, immunophenotype and karyotype. Karyotype was performed in a bone marrow sample by using conventional techniques. In each case, direct method (DM) and/or three cultures were tried. The CM consisted in separating a small part of the material resulting from any of the cultures or DM, preparing slides through cytospin and immunophenotyping through APAAP method using the same monoclonal antibodies (MoAb) as for diagnosis. In 14 cases, the metaphases proved positive to the MoAb: in 4, the cells with abnormality had their origin defined; in other 4 the karyotype was normal preventing any identification; 6 cases had minimal abnormalities not visible through CM; and in two cases abnormal karyotypes were detected only in the cultures with GM-CSF. This study showed that CM is feasible in cases where evident numerical or structural chromosomal abnormalties are present.

scholarly journals Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1098 ◽  
Author(s):  
Yinhsuan Michely Chen ◽  
Shu Qi ◽  
Stephanie Perrino ◽  
Masakazu Hashimoto ◽  
Pnina Brodt
Keyword(s):  
Monoclonal Antibodies ◽  
Insulin Receptor ◽  
Cancer Progression ◽  
Drug Efficacy ◽  
Poor Performance ◽  
Receptor Activation ◽  
Anti Cancer ◽  
Igf I

The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap—a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.

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