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John A Thompson, Robert J Motzer, Ana M Molina, Toni K Choueiri, Elisabeth I Heath, Bruce G Redman, Randeep S Sangha, D Scott Ernst, Roberto Pili, Stella K Kim, Leonard Reyno, Aya Wiseman, Fabio Trave, Banmeet Anand, Karen Morrison, Fernando Doñate, Christian Kollmannsberger
PURPOSE: To determine the safety, pharmacokinetics, and recommendedphase2 dose of an antibody drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: Two phase 1 studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma derived AGS-16M8F and Chinese Hamster Ovary derived AGS-16C3F...
May 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Alexei Gorelik, Antsa Randriamihaja, Katalin Illes, Bhushan Nagar
The ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) enzyme family modulates purinergic signaling by degrading extracellular nucleotides. CD203c (NPP3, ENPP3) regulates the inflammatory response of basophils via ATP hydrolysis and is a marker for allergen sensitivity on the surface of these cells. Multiple other roles and substrates have also been proposed for this protein. In order to gain insight into its molecular functions, we determined the crystal structure of human NPP3 as well as its complex with an ATP analog...
May 2, 2018: FEBS Journal
Qianqian Chen, Aijie Xin, Ronggui Qu, Wenbi Zhang, Lu Li, Junling Chen, Xiang Lu, Yongwei Gu, Jing Li, Xiaoxi Sun
Ectonucleotide pyrophosphatase-phosphodiesterase 3 (ENPP3), a protein detected in the human uterus, has been found to play an important role in the development and invasion of tumours. It was recently discovered that ENPP3 was upregulated during the window of implantation in the human endometrium but its functional relevance remains elusive. The objective was to determine ENPP3 expression in human endometrium and its roles in endometrial receptivity and embryo implantation. ENPP3 expression was analysed using immunohistochemistry and western blot assay...
April 4, 2018: Reproduction, Fertility, and Development
Hui Zhao, John Atkinson, Sara Gulesserian, Zhilan Zeng, Jenny Nater, Jimmy Ou, Peng Yang, Karen Morrison, Jeffrey Coleman, Faisal Malik, Pia Challita-Eid, Sher Karki, Hector Aviña, René Hubert, Linnette Capo, Josh Snyder, Sung-Ju Moon, Roland Luethy, Brian A Mendelsohn, David R Stover, Fernando Doñate
AGS-16C3F is an antibody-drug conjugate (ADC) against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) containing the mcMMAF linker-payload currently in development for treatment of metastatic renal cell carcinoma. AGS-16C3F and other ADCs have been reported to cause ocular toxicity in patients by unknown mechanisms. To investigate this toxicity, we developed an in vitro assay using human corneal epithelial cells (HCEC) and show that HCECs internalized AGS-16C3F and other ADCs by macropinocytosis, causing inhibition of cell proliferation...
April 15, 2018: Cancer Research
Carla Trapero, Lluis Jover, Maria Eulàlia Fernández-Montolí, Amparo García-Tejedor, August Vidal, Inmaculada Gómez de Aranda, Jordi Ponce, Xavier Matias-Guiu, Mireia Martín-Satué
PROBLEM: The diagnosis of endometriosis, a prevalent chronic disease with a strong inflammatory component, is usually delayed due to the lack of noninvasive diagnostic tests. Purinergic signaling, a key cell pathway, is altered in many inflammatory disorders. The aim of the present work was to evaluate the levels of adenosine deaminase (ADA), alkaline phosphatase (ALP), ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and ENPP3, elements of purinergic signaling, as biomarker candidates for endometriosis...
February 2018: American Journal of Reproductive Immunology: AJRI
K L Moek, D J A de Groot, E G E de Vries, R S N Fehrmann
Background: Antibody-drug conjugates (ADCs), consisting of an antibody designed against a specific target at the cell membrane linked with a cytotoxic agent, are an emerging class of therapeutics. Because ADC tumour cell targets do not have to be drivers of tumour growth, ADCs are potentially relevant for a wide range of tumours currently lacking clear oncogenic drivers. Therefore, we aimed to define the landscape of ADC targets in a broad range of tumours. Materials and methods: PubMed and ClinicalTrials...
December 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Hui Zhao, Sara Gulesserian, Sathish Kumar Ganesan, Jimmy Ou, Karen Morrison, Zhilan Zeng, Veronica Robles, Josh Snyder, Lisa Do, Hector Aviña, Sher Karki, David R Stover, Fernando Doñate
Thrombocytopenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADCs), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and Trastuzumab emtansine (T-DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MKs) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers...
June 27, 2017: Molecular Cancer Therapeutics
Lin Lyu, Baolu Wang, Chaoyang Xiong, Xiaotian Zhang, Xiaoyan Zhang, Junjie Zhang
Autotaxin (ATX) or ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) is a secretory glycoprotein and functions as the key enzyme for lysophosphatidic acid generation. The mechanism of ATX protein trafficking is largely unknown. Here, we demonstrated that p23, a member of the p24 protein family, was the protein-sorting receptor required for endoplasmic reticulum (ER) export of ATX. A di-phenylalanine (Phe-838/Phe-839) motif in the human ATX C-terminal region was identified as a transport signal essential for the ATX-p23 interaction...
April 28, 2017: Journal of Biological Chemistry
Yoki Furuta, Shih-Han Tsai, Makoto Kinoshita, Kosuke Fujimoto, Ryu Okumura, Eiji Umemoto, Yosuke Kurashima, Hiroshi Kiyono, Hisako Kayama, Kiyoshi Takeda
Extracellular adenosine 5'-triphosphate (ATP) performs multiple functions including activation and induction of apoptosis of many cell types. The ATP-hydrolyzing ectoenzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (E-NPP3) regulates ATP-dependent chronic allergic responses by mast cells and basophils. However, E-NPP3 is also highly expressed on epithelial cells of the small intestine. In this study, we showed that E-NPP3 controls plasmacytoid dendritic cell (pDC) numbers in the intestine through regulation of intestinal extracellular ATP...
2017: PloS One
Fei-Xue Li, Jiao-Jiao Yu, Ying Liu, Xiao-Ping Miao, Thomas E Curry
Ectonucleotide pyrophosphatase/phosphodiesterase 3 ( Enpp3) is involved in multiple physiological processes, such as morphological changes and inflammatory processes. The present study investigated the spatiotemporal expression pattern and regulatory mechanisms controlling expression of Enpp3 in the rat ovary during the periovulatory period. Immature female rats were injected with pregnant mare serum gonadotropin to stimulate follicular development. Ovaries, granulosa cells, or theca-interstitial cells were collected at various times after human chorionic gonadotropin (hCG) administration...
July 2017: Reproductive Sciences
Nageswara Rao Boggavarapu, Sujata Lalitkumar, Vijay Joshua, Sergo Kasvandik, Andres Salumets, Parameswaran Grace Lalitkumar, Kristina Gemzell-Danielsson
The complexity of endometrial receptivity at the molecular level needs to be explored in detail to improve the management of infertility. Here, differential expression of transcriptomes in receptive endometrial glands and stroma revealed Ectonucleotide Pyrophosphatase/Phosphodiesterase 3 (ENPP3) as a progesterone regulated factor and confirmed by various methods, both at mRNA and protein level. The involvement of ENPP3 in embryo attachment was tested in an in vitro model for human embryo implantation. Interestingly, there was high expression of ENPP3 mRNA in stroma but not protein...
September 26, 2016: Scientific Reports
Sarah Schrödter, Martin Braun, Isabella Syring, Niklas Klümper, Mario Deng, Doris Schmidt, Sven Perner, Stefan C Müller, Jörg Ellinger
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is among the most common human malignancies. METHODS: In order to provide better understanding of the molecular biology of ccRCC and to identify potential diagnostic/prognostic biomarker and therapeutic targets, we utilized a microarray to profile mRNA expression of corresponding normal and malignant renal tissues. Real-time PCR, Western Blot and immunohistochemistry were applied to study the expression of candidate biomarkers...
February 2, 2016: Molecular Cancer
Fernando Doñate, Arthur Raitano, Kendall Morrison, Zili An, Linnette Capo, Hector Aviña, Sher Karki, Karen Morrison, Peng Yang, Jimmy Ou, Ryuichi Moriya, Yuriy Shostak, Faisal Malik, Rossana Nadell, Wendy Liu, Daulet Satpayev, John Atkinson, Ingrid B J Joseph, Daniel S Pereira, Pia M Challita-Eid, David R Stover
PURPOSE: New cancer-specific antigens are required for the design of novel antibody-drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy. EXPERIMENTAL DESIGN: Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen. Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3...
April 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Isabel R Orriss, Michelle L Key, Mark O R Hajjawi, José L Millán, Timothy R Arnett
Previous work has shown that acidosis prevents bone nodule formation by osteoblasts in vitro by inhibiting mineralisation of the collagenous matrix. The ratio of phosphate (Pi ) to pyrophosphate (PPi ) in the bone microenvironment is a fundamental regulator of bone mineralisation. Both Pi and PPi , a potent inhibitor of mineralisation, are generated from extracellular nucleotides by the actions of ecto-nucleotidases. This study investigated the expression and activity of ecto-nucleotidases by osteoblasts under normal and acid conditions...
December 2015: Journal of Cellular Physiology
Brian L Hood, Baoquan Liu, Addie Alkhas, Yutaka Shoji, Rusheeswar Challa, Guisong Wang, Susan Ferguson, Julie Oliver, Dave Mitchell, Nicholas W Bateman, Christopher M Zahn, Chad A Hamilton, Mark Payson, Bruce Lessey, Asgerally T Fazleabas, G Larry Maxwell, Thomas P Conrads, John I Risinger
Despite its importance in reproductive biology and women's health, a detailed molecular-level understanding of the human endometrium is lacking. Indeed, no comprehensive studies have been undertaken to elucidate the important protein expression differences between the endometrial glandular epithelium and surrounding stroma during the proliferative and midsecretory phases of the menstrual cycle. We utilized laser microdissection to harvest epithelial cells and stromal compartments from proliferative and secretory premenopausal endometrial tissue and performed a global, quantitative mass spectrometry-based proteomics analysis...
April 2015: Biology of Reproduction
Shih Han Tsai, Makoto Kinoshita, Takashi Kusu, Hisako Kayama, Ryu Okumura, Kayo Ikeda, Yosuke Shimada, Akira Takeda, Soichiro Yoshikawa, Kazushige Obata-Ninomiya, Yosuke Kurashima, Shintaro Sato, Eiji Umemoto, Hiroshi Kiyono, Hajime Karasuyama, Kiyoshi Takeda
Crosslinking of the immunoglobulin receptor FcεRI activates basophils and mast cells to induce immediate and chronic allergic inflammation. However, it remains unclear how the chronic allergic inflammation is regulated. Here, we showed that ecto-nucleotide pyrophosphatase-phosphodiesterase 3 (E-NPP3), also known as CD203c, rapidly induced by FcεRI crosslinking, negatively regulated chronic allergic inflammation. Basophil and mast cell numbers increased in Enpp3(-/-) mice with augmented serum ATP concentrations...
February 17, 2015: Immunity
J Seo, J S Osorio, E Schmitt, M N Corrêa, G Bertoni, E Trevisi, J J Loor
The liver plays a central role in allowing dairy cattle to make a successful transition into lactation. In liver, as in other tissues, extracellular nucleotides and nucleosides trigger cellular responses through adenosine and ATP receptors. Adenosine triphosphate and certain nucleotides serve as signals that can heighten purinergic receptor activation in several pathologic processes. We evaluated the mRNA expression of genes associated with the purinergic signaling network in liver tissue during the peripartal period...
February 2014: Journal of Dairy Science
Hiroaki Korekane, Jong Yi Park, Akio Matsumoto, Kazuki Nakajima, Shinji Takamatsu, Kazuaki Ohtsubo, Yasuhide Miyamoto, Shinya Hanashima, Kenji Kanekiyo, Shinobu Kitazume, Yoshiki Yamaguchi, Ichiro Matsuo, Naoyuki Taniguchi
Our previous studies on a β1,6-N-acetylglucosaminyltransferase, GnT-IX (GnT-Vb), a homolog of GnT-V, indicated that the enzyme has a broad GlcNAc transfer activity toward N-linked and O-mannosyl glycan core structures and that its brain-specific gene expression is regulated by epigenetic histone modifications. In this study, we demonstrate the existence of an endogenous inhibitory factor for GnT-IX that functions as a key regulator for GnT-IX enzymatic activity in Neuro2a (N2a) cells. We purified this factor from N2a cells and found that it is identical to ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3), as evidenced by mass spectrometry and by the knockdown and overexpression of ENPP3 in cultured cells...
September 27, 2013: Journal of Biological Chemistry
Trude H Agesen, Anita Sveen, Marianne A Merok, Guro E Lind, Arild Nesbakken, Rolf I Skotheim, Ragnhild A Lothe
BACKGROUND AND AIMS: Several clinical factors have an impact on prognosis in stage II colorectal cancer (CRC), but as yet they are inadequate for risk assessment. The present study aimed to develop a gene expression classifier for improved risk stratification of patients with stage II CRC. METHODS: 315 CRC samples were included in the study. Gene expression measurements from 207 CRC samples (stage I-IV) from two independent Norwegian clinical series were obtained using Affymetrix exon-level microarrays...
November 2012: Gut
Fernanda C Vuaden, Luiz Eduardo B Savio, Denise B Ramos, Emerson A Casali, Maurício R Bogo, Carla D Bonan
Extracellular adenosine 5'-triphosphate (ATP) acts as a proinflammatory mediator. Adenosine, the final product of ATP breakdown, is an anti-inflammatory compound, acting mainly on adenosine A(2A) receptors. Considering that the kidney is an organ strongly affected during systemic inflammatory responses and that ectonucleotidases are responsible for the control of extracellular nucleotide and nucleoside levels, we examined the endotoxin-induced effects on ectonucleotidases in kidney membranes of mice, and whether CGS-21680 hydrochloride (3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid), a selective adenosine A(2A) receptor agonist, antagonizes the lipopolysaccharide (LPS)-induced effects on nucleotide catabolism in kidney...
January 15, 2012: European Journal of Pharmacology
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