Inhibition of tumor growth in vitro and in vivo by a monoclonal antibody against human chorionic gonadotropin β

2007 ◽  
Vol 114 (2) ◽  
pp. 94-102 ◽  
Author(s):  
Ning Yu ◽  
Wei Xu ◽  
Zhenggang Jiang ◽  
Qinghua Cao ◽  
Yiwei Chu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Inhibition Of Tumor Growth

Human chorionic gonadotropin improves endometrial receptivity by increasing the expression of homeobox A10

2020 ◽  
Vol 26 (6) ◽  
pp. 413-424
Author(s):  
Mengchen Zhu ◽  
Shanling Yi ◽  
Xiaomin Huang ◽  
Junan Meng ◽  
Haixiang Sun ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Embryo Implantation ◽  
Endometrial Receptivity ◽  
Endometrial Stromal Cells ◽  
Healthy Control ◽  
Hcg Receptor ◽  
Methyltransferase 1

Abstract Homeobox A10 (HOXA10) is a characterized marker of endometrial receptivity. The mechanism by which hCG intrauterine infusion promotes embryo implantation is still unclear. This study seeks to investigate whether hCG improves endometrial receptivity by increasing expression of HOXA10. HOXA10 expression with human chorionic gonadotropin stimulation was analyzed in vitro and in vivo. Our results demonstrate that HOXA10 was decreased in the endometria of recurrent implantation failure patients compared to that in the healthy control fertile group, also we observed that hCG intrauterine infusion increased endometrial HOXA10 expression. HOXA10, blastocyst-like spheroid expansion area was increased, whereas DNA (cytosine-5-)-methyltransferase 1 was decreased when human endometrial stromal cells (hESCs) were treated with 0.2 IU/ml of hCG for 48 h. HOXA10 promoter methylation was also reduced after hCG treatment. Collagen XV (ColXV) can repress the expression of DNA (cytosine-5-)-methyltransferase 1, and hCG treatment increased the expression of ColXV. However, when the hESCs were treated with LH/hCG receptor small interfering RNA to knock down LH/hCG receptor, hCG treatment failed to repress DNA (cytosine-5-)-methyltransferase 1 expression or to increase ColXV expression. Our findings suggest that hCG may promote embryo implantation by increasing the expression of HOXA10.

Inhibition of tumor growth induced by histamine: In vivo and in vitro studies

1993 ◽  
Vol 38 (3-4) ◽  
pp. C175-C177 ◽  
Author(s):  
G. P. Cricco ◽  
C. A. Davio ◽  
R. M. Bergoc ◽  
E. S. Rivera
Keyword(s):  
Tumor Growth ◽  
In Vitro Studies ◽  
Inhibition Of Tumor Growth

HCD122, an Antagonist Human Anti-CD40 Monoclonal Antibody, Enhances Efficacy of CHOP in Tumor Xenograft Model of Human Diffuse Large B-Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 528-528 ◽  
Author(s):  
Mohammad Luqman ◽  
Ssucheng J. Hsu ◽  
Matthew Ericson ◽  
Sha Klabunde ◽  
Seema Kantak
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Tumor Growth ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract HCD122 (formerly known as CHIR-12.12), is a fully human anti-CD40 monoclonal antibody (mAb) currently in Phase I clinical trials for treatment of chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). An IgG1 antibody selected for its potency as an antagonist of the CD40 signaling pathway, HCD122 both inhibits CD40/CD40L-stimulated growth of lymphoma cells ex vivo, and mediates highly effective Antibody Dependent Cell-mediated Cytotoxicity (ADCC) in vitro. As a single agent, HCD122 exhibits potent anti-tumor activity in vivo, in preclinical models of MM, Hodgkin’s lymphoma, Burkitt’s lymphoma, mantle cell lymphoma and diffused large B-cell lymphoma (DLBCL). Although several therapeutic antibodies approved for treatment of Non-Hodgkin’s Lymphoma have clinical activity as single agents, combining these antibodies with standard-of-care chemotherapeutic regimens such as CHOP (cytoxan, vincristine, doxorubicin and prednisone) is proving optimal for both increasing response rates and extending survival, and antibodies currently in clinical development are likely to be used in combination therapies in the future. Therefore the studies reported here examine the effects of combining HCD122 with CHOP, the standard for treatment of high grade NHL, in in vitro and in vivo models of DLBCL. In the xenograft RL model of DLBCL, HCD122 administered intraperitoneally weekly at 1 mg/kg as a single agent, or in combination with CHOP (H-CHOP), and CHOP alone all significantly reduced tumor growth at day 25 when compared to treatment with huIgG1 control antibody (P<0.001). However, tumor growth delay (time to reach tumor size of 500 mm3) was significantly longer for H-CHOP (17.5 days), than for CHOP (8 days) or HCD122 (6 days) (p < 0.001). No toxicity was observed with the H-CHOP combination. Interestingly, at the end of the study (day 35), reduction in tumor growth was significantly greater in the treatment group that received H-CHOP than the groups that received either 10 mg/kg Rituxan plus CHOP (R-CHOP) (p < 0.05) or CHOP alone (p < 0.001). These data show that in this model, treatment with the combination H-CHOP results in greater anti-tumor efficacy than with either modality alone or R-CHOP. We have observed that in vitro, exposure to CD40 Ligand (CD40L) results in aggregation of DLBCL cells, and postulate that interfering with the ability of cancer cells to adhere and interact with each other and their microenvironment may potentiate the effect of chemotherapeutics. To elucidate the mechanism by which the combination of HCD122 and CHOP enhanced efficacy in vivo, we developed an in vitro system to examine the effects of HCD122 on the expression of adhesion molecules in the RL and SU-DHL-4 cell lines. In these studies, HCD122 inhibited CD40L-induced expression of CD54, CD86 and CD95 in both cell lines, as well as aggregation of SU-DHL-4 cells. The combined effect of each of the components of CHOP with HCD122 in three-dimensional spheroid cultures is currently under investigation. These data provide a therapeutic rationale for combination of HCD122 with CHOP in DLBCL clinical trials.

The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13093-13093 ◽  
Author(s):  
S. L. Smiley ◽  
D. O. Henry ◽  
M. K. Wong
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Receptor System ◽  
Fgf Receptor ◽  
Tumor Inhibition ◽  
Inhibition Of Tumor Growth

13093 Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin > tinzaparin > enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells. No significant financial relationships to disclose.

Effects of the antiandrogen hydroxyflutamide on progesterone secretion by preovulatory rat follicles in vivo and in vitro

1991 ◽  
Vol 69 (9) ◽  
pp. 1288-1293 ◽  
Author(s):  
Yallampalli Chandrasekhar ◽  
David T. Armstrong
Keyword(s):  
Luteinizing Hormone ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Serum Progesterone ◽  
Antagonistic Action ◽  
Lh Surge ◽  
Progesterone Secretion ◽  
Preovulatory Follicles

Serum and ovarian progesterone levels and in vitro production of progesterone by preovulatory follicles were measured on proestrus in pregnant mare's serum gonadotropin (PMSG) primed immature rats in which the luteinizing hormone (LH) surge and ovulation were blocked by administration of the antiandrogen hydroxyflutamide. Serum progesterone levels observed at 12:00 on proestrus were significantly elevated, twofold above those observed in vehicle-treated controls, by in vivo administration of 5 mg hydroxyflutamide 4 h earlier. In control rats, proestrous progesterone did not increase until 16:00, in parallel with rising LH levels of the LH surge. No LH surge occurred in the hydroxyflutamide-treated rats, ovulation was blocked, and serum progesterone declined throughout the afternoon of proestrus, from the elevated levels present at 12:00. Administration of human chorionic gonadotropin (hCG) at 11:00 advanced the elevation of serum progesterone by 2 h in vehicle-treated controls and prevented the decline in progesterone levels in hydroxyfiutamide-treated rats. The patterns of change in ovarian tissue concentrations with time and treatment were essentially similar to those observed for serum progesterone. In in vitro experiments, progesterone secretion during 24 h culture of preovulatory follicles obtained on PMSG-induced proestrus was significantly increased, sixfold, by addition to the culture media of 370 μM but not of 37 μM hydroxyflutamide. Testosterone (50 nM) and hCG (20 mIU/mL) caused 26- and 14-fold increases, respectively, in progesterone secretion by cultured follicles. Hydroxyflutamide significantly reduced the stimulatory effect of testosterone but not of hCG on progesterone secretion in vitro. These results suggest that the antiandrogen hydroxyflutamide stimulates progesterone secretion, both in vivo and in vitro, through an initial androgen-agonistic action, before its antagonistic action is expressed. Its androgen-antagonistic action is responsible for its ability to inhibit testosterone-induced progesterone secretion in vitro. Its failure to reduce hCG-stimulated progesterone secretion in vivo and in vitro indicates that the latter stimulation is exerted independently of, and not as a consequence of, androgen action. The decrease in serum progesterone levels on the afternoon of proestrus therefore appears to be a consequence rather than a cause of the absence of an LH surge in the hydroxyflutamide-treated rats. It is concluded that the inhibitory effect of hydroxyflutamide on the preovulatory LH surge and ovulation is due not to inhibition of progesterone secretion at the ovarian level but most likely to neuroendocrine site(s) of action of the inhibitor.Key words: antiandrogen, hydroxyflutamide, progesterone, luteinizing hormone, ovulation, human chorionic gonadotropin.

Reduction of Testicular Human Chorionic Gonadotropin Receptors by Human Chorionic Gonadotropin in vivo and in vitro

1988 ◽  
Vol 29 (4) ◽  
pp. 156-161 ◽  
Author(s):  
Mikio Namiki ◽  
Masaya Kitamura ◽  
Norio Nonomura ◽  
Masahiro Nakamura ◽  
Akihiko Okuyama ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Gonadotropin Receptors

scholarly journals First Preclinical Report of the Efficacy and PD Results of KHK2823, a Non-Fucosylated Fully Human Monoclonal Antibody Against IL-3Rα

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1349-1349 ◽  
Author(s):  
Tadakazu Akiyama ◽  
Shin-ichiro Takayanagi ◽  
Yoshimi Maekawa ◽  
Kohta Miyawaki ◽  
Fumiaki Jinnouchi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Tumor Growth ◽  
Rat Model ◽  
Research Funding ◽  
Tumor Xenograft ◽  
Cynomolgus Monkeys ◽  
Nude Rat

Abstract Human interleukin-3 receptor alpha (IL-3Ra, CD123), which promotes the proliferation and differentiation of hematopoietic cells, is highly expressed in myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We newly generated KHK2823, a non-fucosylated fully human IgG1 monoclonal antibody against human IL-3Ra, by utilizing the POTELLIGENT® technology. Here, we describe the in vitro and in vivo preclinical efficacy and safety of KHK2823, as well as its pharmacodynamic (PD) profile. At first, we explored that KHK2823 bound to various hematological malignant cells and leukemic stem cells. The cells from AML and MDS bone marrows were found to be bound by KHK2823. A significant part of bone marrow cells derived from B-cell acute lymphoblastic leukemia (B-ALL) patients was also bound by KHK2823. KHK2823 bound to soluble human IL-3Ra protein with a sub-nanomolar dissociation constant (KD), and recognized CD34+ CD38+ (leukemic blast) and/or CD34+ CD38- (leukemic stem cell) cells in patients with AML/MDS, as well as AML cell lines, thereby obtaining a high antibody-dependent cellular cytotoxic activity without complement-dependent cytotoxicity. Interestingly, KHK2823 did not interfere with the binding of IL-3 to IL-3R. The lack of a receptor-ligand interaction may conserve the IL-3 signal, which plays an important role in normal hematopoiesis. In a tumor model xenografting the human AML cell line MOLM-13 on nude rats, KHK2823 significantly suppressed the tumor growth at doses of 0.1 and 1 mg/kg (Figure 1). The PD and toxicity profiles of KHK2823 were assessed in cynomolgus monkeys administered at doses ranging from 0.1 to 100 mg/kg by i.v. infusion, once weekly for 4 weeks. KHK2823 was generally well tolerated in monkeys, even at 100 mg/kg. The number of IL-3Ra-positive cells in the peripheral blood of cynomolgus monkeys decreased in all groups receiving KHK2823, which suggest KHK2823 could exert its depletion activity of IL-3Ra-positive cells in human (Figure 2). Currently, the safety and tolerability of KHK2823 is being investigated in patients with AML or MDS in a Phase 1 study (NCT02181699, https://clinicaltrials.gov/ct2/show/NCT02181699). This is the first non-randomized, open-label, dose escalation clinical study to investigate the safety, PK, immunogenicity and PD of repeated doses of KHK2823. In summary, KHK2823 was confirmed to bind to AML, MDS and B-ALL cells as the IL-3Ra in accordance with other publications. KHK2823 was also found to eliminate AML cells in vitro and also suppressed the AML tumor growth in the in vivo model. In addition, the number of IL-3Ra-positive cells in cynomolgus monkeys decreased following i.v. infusion of 0.1mg/kg KHK2823 with a tolerable safety profile, even at a dose of 100 mg/kg. Taken together, KHK2823 may therefore be a promising anti-IL-3Ra therapeutic drug for the treatment of AML. Figure 1. Antitumor activity of KHK2823 in a tumor xenograft nude rat model Figure 1. Antitumor activity of KHK2823 in a tumor xenograft nude rat model Figure 2. PD profile of KHK2823 in cynomolgus monkeys Figure 2. PD profile of KHK2823 in cynomolgus monkeys Disclosures Akiyama: Kyowa Hakko Kirin Co., Ltd.: Employment. Takayanagi:Kyowa Hakko Kirin Co., Ltd.: Employment. Maekawa:Kyowa Hakko Kirin Co., Ltd.: Employment. Shimabe:Kyowa Hakko Kirin Co., Ltd.: Employment. Nishikawa:Kyowa Hakko Kirin Co., Ltd.: Employment. Yamawaki:Kyowa Hakko Kirin Co., Ltd: Employment. Iijima:Kyowa Hakko Kirin Co., Ltd: Employment. Hiura:Kyowa Hakko Kirin Co., Ltd.: Employment. Takahashi:Kyowa Hakko Kirin Co., Ltd.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Tawara:Kyowa Hakko Kirin Co., Ltd: Employment.

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