Showing papers by "Chiron Corporation published in 2007"

The course of hepatitis C viraemia in transfusion recipients prior to availability of antiviral therapy

Abstract: Summary. Knowing the likely distribution of intervals from hepatitis C infection to first RNA-negativity is important in deciding about therapeutic intervention. Prospectively collected sera and data from the Transfusion-transmitted Viruses Study (1974–1980) provide specific dates of infection and pattern of alanine aminotransferase (ALT) elevations. We examined frequency, timing and correlates of spontaneous resolution for 94 acutely infected transfusion recipients followed for a median of 9.5 months. Later, follow-up sera (>10 years) were available for 27 of the 94 cases from a Veterans Administration (VA) Study (1989–1990). Twenty-five (27%) of the 94 cases were classified as probably resolved during the episode itself. First RNA negativity occurred at 6–50 weeks (median, 19.5 weeks) after infection, and 5–43 weeks (median, 11 weeks) after ALT elevation. Thirteen of the 25 cases remained RNA-negative subsequently; 12 others had 1–6 RNA-positive sera intercalated between first and last RNA-negative results. RNA negativity, therefore, began variably and was interrupted in 12 cases of 25 (48%) by transient RNA-positive sera. Five of these 25 patients who were RNA-negative in the last study specimen had late, Veterans Administration Study follow-up; none showed viraemia. Of the remaining 69 transfusion transmitted virus study recipients, whose last serum was RNA-positive, two cleared viraemia after the last study serum but before late follow-up. Eleven (16%) had 23 intercalated RNA-negative sera before last positivity. RNA status, therefore, needs monitoring for many months before judging the spontaneous outcome as transient negativity may occur. Resolution was significantly more common in women and symptomatic cases; it was not associated with viral load in the infectious donation, HCV genotype, or the recipient’s age.

Recombinant Interleukin-2 Significantly Augments Activity of Rituximab in Human Tumor Xenograft Models of B-cell Non-Hodgkin Lymphoma

Abstract: Recombinant interleukin-2 (rIL-2) is a pleiotropic cytokine that activates select immune effector cell responses associated with antitumor activity, including antibody-dependent cellular cytotoxicity (ADCC). Rituximab is an anti-CD20 monoclonal antibody that activates ADCC in non-Hodgkin lymphoma (N

Protection of rhesus monkeys by a DNA prime/poxvirus boost malaria vaccine depends on optimal DNA priming and inclusion of blood stage antigens.

Abstract: BACKGROUND We have previously described a four antigen malaria vaccine consisting of DNA plasmids boosted by recombinant poxviruses which protects a high percentage of rhesus monkeys against Plasmodium knowlesi (Pk) malaria. This is a multi-stage vaccine that includes two pre-erythrocytic antigens, PkCSP and PkSSP2(TRAP), and two erythrocytic antigens, PkAMA-1 and PkMSP-1(42kD). The present study reports three further experiments where we investigate the effects of DNA dose, timing, and formulation. We also compare vaccines utilizing only the pre-erythrocytic antigens with the four antigen vaccine. METHODOLOGY In three experiments, rhesus monkeys were immunized with malaria vaccines using DNA plasmid injections followed by boosting with poxvirus vaccine. A variety of parameters were tested, including formulation of DNA on poly-lactic co-glycolide (PLG) particles, varying the number of DNA injections and the amount of DNA, varying the interval between the last DNA injection to the poxvirus boost from 7 to 21 weeks, and using vaccines with from one to four malaria antigens. Monkeys were challenged with Pk sporozoites given i.v. 2 to 4 weeks after the poxvirus injection, and parasitemia was measured by daily Giemsa stained blood films. Immune responses in venous blood samples taken after each vaccine injection were measured by ELIspot production of interferon-gamma, and by ELISA. CONCLUSIONS 1) the number of DNA injections, the formulation of the DNA plasmids, and the interval between the last DNA injection and the poxvirus injection are critical to vaccine efficacy. However, the total dose used for DNA priming is not as important; 2) the blood stage antigens PkAMA-1 and PkMSP-1 were able to protect against high parasitemias as part of a genetic vaccine where antigen folding is not well defined; 3) immunization with PkSSP2 DNA inhibited immune responses to PkCSP DNA even when vaccinations were given into separate legs; and 4) in a counter-intuitive result, higher interferon-gamma ELIspot responses to the PkCSP antigen correlated with earlier appearance of parasites in the blood, despite the fact that PkCSP vaccines had a protective effect.

Immune response to conjugated meningococcal C vaccine in pediatric oncology patients

Abstract: Background Following outbreaks of meningococcal disease in Quebec in 1991–1993 and 2000–2001, a mass vaccination campaign was performed. In 2001–2002, children aged 2 months to 20 years were immunized with the Meningococcal CRM197 vaccine (Menjugate™). We examined the response of pediatric oncology patients during or following maintenance chemotherapy and post-bone-marrow transplantation to Meningococcal C vaccine. Procedure This was an open label descriptive study of a cohort of patients from the oncology clinic at the Montreal Children's Hospital. A positive vaccine response was defined as a fourfold increase in specific IgG from baseline and a bactericidal assay using human complement (hBCA) titer >1:4. Results Of the 25 patients with ALL, 13 had a serologic response (average 60-fold increase). The serologic responders had a higher mean B cell count (0.262) compared to non-responders 0.068 × 10.9/L [t(23) = 2.843 (P < 0.05)]. Eleven of the 12 non-responders and 4 of the responders were on maintenance chemotherapy. In addition, two of the five patients post-bone-marrow transplant, responded. Fifteen of the 34 patients (44%) had an adequate hBCA response (mean titer 61). The group included 14/18 serologic responders with hBCA response (P < 0.001) and 16/17 non-serologic responders with no hBCA response (P < 0.001). Conclusions Meningococcal C-conjugate vaccine produced variable responses in children with common cancers. Proximity to chemotherapy and total B cell number may help predict likelihood of response. Pediatr Blood Cancer 2007;49:918–923. © 2007 Wiley-Liss, Inc.

A Series of Collaborations between Various Pharmaceutical Companies and Regulatory Authorities Concerning the Analysis of Biomolecules Using Capillary Electrophoresis: Additional Instruments/Buffer

Abstract: An international project team (including members from US, Canada and UK) was formed from a number of interested biopharmaceutical companies and regulatory authorities to conduct a cross-organisation collaboration exercise. The results of the first comparison with eight different organisations that used instruments of the same equipment model, the same reagents, and the same methodology has been reported previously [1]. This report represents the addition of other instruments using a different run buffer. The relative migration times were different, as expected, prohibiting a direct comparison between companies. The within-organisation variability was low for both relative migration time (<0.34% RSD% for all companies save one) and the peak area (<5% RSD% for all companies save one) when measuring the purity of a representative IgG sample. The apparent molecular weight of bovine serum albumin was measured with good precision (less than 10% RSD% across all companies) to the theoretical value when all data is utilized (67.5 kDa compared to 66.4 kDa). For a representative IgG sample, the three main components, IgG Light Chain, IgG Non-glycosylated Heavy Chain, and IgG Heavy Chain, could not be separated, specifically the IgG Non-glycosylated Heavy Chain and IgG Heavy Chain. When the IgG Non-glycosylated Heavy Chain and IgG Heavy Chain were combined for all organisations, the fractional peak area for the IgG Light Chain and IgG Non-glycosylated Heavy Chain + IgG Heavy Chain peak also showed excellent agreement, with less than 7.5 and 3.5% RSD%, respectively. The value of this exercise is in demonstrating the reliability of CE for the determination of apparent size of biopharmaceutical proteins. This underpins the appropriate use of such CE data in support of regulatory submissions.

EGFH2 genes and gene products

Abstract: This invention relates to mouse and human EGFH2, and to variants thereof and to polynucleotides encoding EGFH2. This invention also relates to therapeutic agents related to the polynucleotides and proteins.

Pancreatic Cancer Genes

Abstract: The present invention provides the art with the DNA coding sequences of polynucleotides that are up-or-down-regulated in cancer and dysplasia. These polynucleotides and encoded proteins or polypeptides can be used in the diagnosis or identification of cancer and dysplasia. Inhibitors of the up-regulated polynucleotides and proteins can decrease the abnormality of cancer and dysplasia. Enhancing the expression of down-regulated polynucleotides or introducing down-regulated proteins to cells can decrease the growth and/or abnormal characteristics of cancer and dysplasia.

Antibodies to a novel antigen in acute hepatitis C virus infections.

Abstract: Background Conformational viral proteins potentially play an important role in the immunobiology of acute hepatitis C virus (HCV) infection and may enable earlier antibody detection. Materials and Methods HCV RNA was detected using nucleic acid testing. Early antibody production was evaluated using three enzyme immunoassays (EIAs) containing antigenic proteins not present in licensed EIAs. Respectively, these contained: 1 multiple-epitope fusion antigen (MEFA) 7·1-NS3/4a, 2 F and Core, and 3 E1/E2 proteins. NS3/4a is a conformational antigen retaining protease and helicase enzymatic activities. MEFA 7·1 contains the linear epitopes used in licenced EIAs, including the latest EIA-3·0, in combination with genotype 1–3 specific epitopes. Forty-two RNA positive, EIA-3·0 negative samples, including two persistently serosilent cases, were used to evaluate these research EIAs. As controls, 54 EIA-3·0 negative/RNA negative and three HCV RNA+/antibody positive specimens were included. Results Only the MEFA 7·1-NS3/4a EIA was positive in seven (17%) of the 42 HCV RNA + specimens, in all three EIA-3·0 positive controls but in none of 54 EIA-3·0 negative/HCV RNA negative controls. Notably, six of the seven (86%) specimens had evidence of active hepatitis (ALT > 210 IU/l). The two serosilent cases were research EIA negative. Conclusion A novel EIA with conformational and linear epitopes detected HCV antibodies in 17% of viraemic specimens missed by the standard reference EIA-3·0. Our research EIA appears to detect HCV antibodies closer to the initiation of acute hepatitis. Given that the average RNA-positive, antibody-negative window period is ∼56·4 days, this 17% yield would translate into a ∼10-day earlier detection of antibodies.

N′-(α-Aminoacyl)- and N′-α-(N-Alkylamino)acyl Derivatives of Vancomycin and Eremomycin: II. Antibacterial Activity of N′-(α-Aminoacyl)- and N′-α-(N-Alkylamino)acyl Derivatives of Vancomycin and Eremomycin

Abstract: N ′-(α-Aminoacyl)- and N ′-α-( N α -Alkylamino)acyl Derivatives of Vancomycin and Eremomycin

The Chemical Development of CHIR-258

Abstract: This paper is a case history of the early stage chemical development of CHIR-258 (4-amino-5-fluoro-3-[6-(4-methyl-1-piperazinyl)-1H-benzimidazol-2-yl]-2(1H)-quinolinone, DL-lactate salt), a vascular endothelial growth factor (VEGF) kinase inhibitor for treatment of solid and hematologic cancers. The article covers various aspects of work in chemical development. In particular we discuss evaluation of the medicinal chemistry route, scale-up, salt preparation, process impurities, in-process control (IPC) method development, supply route development, technology transfer to contract manufacturing organization (CMO) and pilot plant production. Some interesting points regarding regulatory requirement for chemical development are also discussed.

Novel IGF-1 composition and its use

Abstract: A highly concentrated, low salt-containing, biologically active syrup form of IGF-I or variant thereof and methods for its preparation are provided. This novel syrup form of IGF-I has an IGF-I concentration of at least about 250 mg/ml, a density of about 1.0 g/ml to about 1.2 g/ml, and a viscosity of about 13,000 centipoise (cps) to about 19,000 cps, as measured at ambient temperature (23° C.). The IGF-I syrup is prepared by precipitating or partitioning IGF-I from solution, preferably by adjusting the solution pH or by use of a solubility enhancer to concentrate IGF-I in solution followed by removal of the solubility enhancer. The precipitated syrup is useful as a means of storing IGF-I in a stable form and as a means of preparing compositions comprising biologically active IGF-I. Pharmaceutical compositions and kits comprising this concentrated IGF-I syrup are provided. The precipitated IGF-I syrup, IGF-I reconstituted from the IGF-I syrup, pharmaceutical compositions, and kits are useful in IGF-I therapy directed to IGF-I-responsive conditions.

***WITHDRAWN PATENT AS PER THE LATEST USPTO WITHDRAWN LIST***Antibodies to EGFH2 polypeptides

Abstract: This invention relates to mouse and human EGFH2, and to variants thereof and to polynucleotides encoding EGFH2. This invention also relates to therapeutic agents related to the polynucleotides and proteins.