Chiron Corporation

About: Chiron Corporation is a based out in . It is known for research contribution in the topics: Antigen & Hepatitis C virus. The organization has 1973 authors who have published 1969 publications receiving 172330 citations.

Compositions for the inhibition of protein hormone formation and uses thereof

Abstract: Compounds having proteolytic inhibitory activity useful for treating diseases, particularly as applied to the treatment of sepsis, AIDS or autoimmune diseases, resulting from an increase in the circulating level of mature protein hormones derived from the proteolytic cleavage of prohormone precursors, and methods for identifying compounds having the desired inhibitory activity.

Tumor-specific intravenous gene delivery using oncolytic adenoviruses

Abstract: In this report, we describe a vector system that specifically delivers transgene products to tumors following intravenous (i.v.) administration. The Escherichia coli cytosine deaminase (CD) gene was placed in the E3B region of the tumor-selective, replication-competent adenovirus ONYX-411, under the control of endogenous viral late gene regulatory elements. Thus, CD expression was directly coupled to the tumor-selective replication of the viral vector. In vitro, CD was expressed efficiently in various human cancer cell lines tested but not in cultured normal human cells, including human hepatocytes. Following i.v. administration into nude mice carrying human tumor xenografts, robust CD activity was detected only in tumors but not in liver or other normal tissues. Levels of CD activity in the tumors increased progressively following i.v. virus administration, correlating closely with virus replication in vivo. Subsequent administration of 5-fluorocytosine (5-FC) demonstrated a trend to improve the antitumor efficacy of these viruses in a mouse xenograft model, presumably due to the intratumoral conversion of 5-FC to the chemotherapeutic drug 5-fluorouracil. We show that the combination of a highly selective oncolytic virus, ONYX-411, with the strategic use of the viral E3B region for transgene insertion provides a powerful platform that allows for tumor-specific, persistent and robust transgene expression after i.v. administration. This technology provides an opportunity to enhance greatly both safety and efficacy of cancer gene therapy.

In Vitro Cytotoxic Targeting by Human Mononuclear Cells and Bispecific Antibody 2B1, Recognizing c-erbB-2 Protooncogene Product and Fcγ Receptor III

Abstract: Bispecific murine monoclonal antibody 2B1, possessing dual specificity for the human c- erb B-2 protooncogene product and human Fcγ receptor III (CD16) was evaluated for the ability to promote specific lysis of c- erb B-2-positive tumor cells in vitro . In short-term 51Cr release assays with human mononuclear cells as effectors and SK-Br-3 human breast cancer cells as targets, neither parental antibody of 2B1 mediated significant specific lysis, but bispecific antibody was as active as a chemical heteroconjugate, with 5 ng/ml of 2B1 causing half-maximal lysis at an effector/target ratio of 20:1 and 2 ng/ml 2B1 causing half-maximal lysis at an E/T ratio of 40:1. The cytotoxic targeting activity of 2B1 F(ab′)2 fragment was the same as that of whole bispecific antibody, and the activity of whole 2B1 was not reduced when assays were performed in 100% autologous human serum, indicating that 2B1 binds effector cells through the CD16-binding site derived from parental antibody 3G8 rather than through its Fc portion. Variable inhibition of 2B1-mediated lysis was observed when autologous polymorphonuclear leukocytes from different donors were added to mononuclear effector cells at a 2:1 ratio; this inhibition was overcome at higher antibody concentration. 2B1 bispecific monoclonal antibody was also able to mediate targeted cytolysis using whole human blood as a source of effector cells or using effector or target cells derived from ovarian cancer patients.

A mathematical model of sialylation of N-linked oligosaccharides in the trans-Golgi network

Abstract: A mathematical model is developed of the compartmentalized sialylation of N-Iinked oligosaccharides in order to understand and predict the outcome of sialylation reactions. A set of assumptions are presented, including Michaelis-Menten-type dependency of reaction rate on the concentration of the glycoprotein substrate. The resulting model predicts the heterogeneous outcome of a posttranslational oligosaccharide biosynthesis step, a critical aspect that is not accounted for in the modeling of the cotranslational attachment of oligosacchari des to glycosylation sites (Shelikoff et aL, Biotech. Bioeng., 50, 73-90, 1996) or general models of the secretion process (Noe and Delenick, J. Cell Set, 92, 449-459, 1989). In the steady-state for the likely case where the concentration of substrate is much less than the K,,, of the sialyltransferase, the model predicts that the extent of sialylation, x, will depend upon the enzyme concentration, enzyme kinetic parameters and substrate residence time in the reaction compartment The value of x predicted by the model using available literature data is consistent with the values of x that have been recently determined for the glycoproteins CD4 (Spelhnan et aL, Biochemistry, 30, 2395-2406,1991) and t-PA (Spelhnan et aL, J. BioL Chem., 1M, 14100-14111, 1989) secreted by Chinese hamster ovary cells. For the unsaturated case, the model also predicts that x is independent of the concentration of secreted glycoprotein in the Golgi. The general modeling approach outlined in this article may be applicable to other glycosylation reactions and posttranslational modifications.