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ImClone Systems Incorporated is a formerly independent biopharmaceutical company dedicated to developing biologic medicines in the area of oncology. It was founded in 1984 and has its corporate headquarters in Bridgewater, New Jersey and its research headquarters in New York City. On October 6, 2008, it accepted a $6.5 billion acquisition offer from Eli Lilly and Company, and became a fully owned subsidiary of Eli Lilly and Company on November 24, 2008. Prior to the acquisition, it was traded on the NASDAQ stock exchange under the symbol IMCL. In 2014 the use of the ImClone brand name was retired and the former ImClone research and manufacturing sites were renamed Eli Lilly and Company. Wikipedia.

Huang C.S.,Columbia University | Sadre-Bazzaz K.,Columbia University | Shen Y.,Columbia University | Shen Y.,Imclone Systems | And 4 more authors.
Nature | Year: 2010

Propionyl-coenzyme A carboxylase (PCC), a mitochondrial biotin-dependent enzyme, is essential for the catabolism of the amino acids Thr, Val, Ile and Met, cholesterol and fatty acids with an odd number of carbon atoms. Deficiencies in PCC activity in humans are linked to the disease propionic acidaemia, an autosomal recessive disorder that can be fatal in infants 1-4. The holoenzyme of PCC is an α6β 6 dodecamer, with a molecular mass of 750 kDa. The α-subunit contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, whereas the β-subunit supplies the carboxyltransferase (CT) activity. Here we report the crystal structure at 3.2-Å resolution of a bacterial PCC α 6β6 holoenzyme as well as cryo-electron microscopy (cryo-EM) reconstruction at 15-Å resolution demonstrating a similar structure for human PCC. The structure defines the overall architecture of PCC and reveals unexpectedly that the α-subunits are arranged as monomers in the holoenzyme, decorating a centralβ6 hexamer. A hitherto unrecognized domain in the α-subunit, formed by residues between the BC and BCCP domains, is crucial for interactions with the β-subunit. We have named it the BT domain. The structure reveals for the first time the relative positions of the BC and CT active sites in the holoenzyme. They are separated by approximately 55Å, indicating that the entire BCCP domain must translocate during catalysis. The BCCP domain is located in the active site of the β-subunit in the current structure, providing insight for its involvement in the CT reaction. The structural information establishes a molecular basis for understanding the large collection of disease-causing mutations in PCC and is relevant for the holoenzymes of other biotin-dependent carboxylases, including 3-methylcrotonyl-CoA carboxylase (MCC)5-7 and eukaryotic acetyl-CoA carboxylase (ACC). © 2010 Macmillan Publishers Limited. All rights reserved.

Belardi V.,University of Pisa | Gallagher E.J.,Mount Sinai School of Medicine | Novosyadlyy R.,Imclone Systems | Leroith D.,Mount Sinai School of Medicine
Journal of Mammary Gland Biology and Neoplasia | Year: 2013

Obesity and the Metabolic Syndrome are associated with multiple factors that may cause an increased risk for cancer and cancer-related mortality. Factors involved include hyperinsulinemia, hyperglycemia, hyperlipidemia and IGFs. Insulin resistance is also associated with alterations in the levels of proinflammatory cytokines, chemokines, adipokines (leptin, adiponectin) that may also be contributing factors. The insulin family of proteins is ubiquitously expressed and has pleiotropic effects on metabolism and growth. However insulin, IGF-1 and particularly IGF-2 have been identified as tumor promoters in multiple studies. Mouse models have focused on insulin and IGF-1 and their receptors as being involved in tumor progression and metastases. The role of the insulin receptor as either mediating the effects on tumors or as compensating for the insulin-like growth factor receptor has arisen. Its role has been supported by preclinical studies and the importance of insulin resistance and hyperinsulinemia in obesity and early diabetes. Since the focus of this review is the insulin-family we will focus on insulin, IGF-1 and IGF-2. © 2013 Springer Science+Business Media New York.

Protein biopharmaceuticals, such as monoclonal antibodies (mAbs) are widely used for the prevention and treatment of various diseases. The complex and lengthy upstream and downstream production methods of the antibodies make them susceptible to physical and chemical modifications. Several IgG1 immunoglobulins are used as medical agents for the treatment of colon, breast, and head and neck cancers, and at least four to eight isoforms exist in the products. The regulatory agencies understand the complex nature of the antibody molecules and allow the manufactures to set their own specifications for lot release, provided the safety and efficacy of the products are established in animal models prior to clinical trials. During the manufacture of a mAb product, we observed lot-to-lot variability in the isoform content and, although the variability is within the set specifications for lot release, made attempts to gain mechanistic insight by isolating and characterizing the individual isoforms. Matrix-assisted laser desorption/ionization (MALDI) and liquid chromatography (LC)/mass spectrometry (MS)/MS analyses of the isolated isoforms indicate that this variability is caused by sialic acid content, as well as truncation of C-terminal lysine of the individual isoforms. Sialidase and carboxypeptidase treatment of the product confirm the observations made by MALDI and LC/MS/MS.

Yuen D.,University of California at Berkeley | Pytowski B.,Imclone Systems | Chen L.,University of California at Berkeley
Investigative Ophthalmology and Visual Science | Year: 2011

PURPOSE. Lymphangiogenesis (LG) accompanies many corneal diseases after inflammatory, infectious, or chemical insults and is a primary mediator of transplant rejection. The purpose of this study was to investigate whether there is a time window for therapeutic intervention of corneal LG and whether a combined blockade of VEGFR-2 and VEGFR-3 effectively suppresses early-, middle-, or late-stage LG. METHODS. Corneal inflammatory neovascularization was induced by a standard suture placement model in mice. Neutralizing antibodies against VEGFR-3 and/or VEGFR-2 were administrated systemically with the treatment started at postoperative day 0, day 7, or day 14. Whole mount corneas were sampled for immunofluorescence microscopic studies using LYVE-1 (a lymphatic marker) antibodies. Digital images were analyzed by software. RESULTS. Both VEGFR-3 and VEGFR-2 were involved in corneal suture-induced inflammatory LG. Their combined blockade led to a significant inhibition of both early- and middle-stage LG while demonstrating no effect on late-stage LG. CONCLUSIONS. Corneal inflammatory LG has a discrete time window for intervention therapy. Although it is important to start the treatment as soon as possible, interventions initiated in the middle of the LG process are still effective. These novel findings will shed some light on our understanding of inflammatory LG and the development of new therapeutic protocols for LG-related diseases at different stages. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

Novosyadlyy R.,Imclone Systems | Leroith D.,Mount Sinai School of Medicine | Leroith D.,Haifa University
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2012

Numerous lines of evidence indicate that insulin-like growth factor signaling plays an important role in the regulation of life span and tumor development. In the present paper, the role of individual components of insulin-like growth factor signaling in aging and tumor development has been extensively analyzed. The molecular mechanisms underlying aging and tumor development are frequently overlapping. Although the link between reduced insulin-like growth factor signaling and suppressed tumor growth and development is well established, it remains unclear whether extended life span results from direct suppression of insulin-like growth factor signaling or this effect is caused by indirect mechanisms such as improved insulin sensitivity. © 2011 The Author.

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