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Methods and compositions for the prevention and treatment of sepsis

一种组合物、败血症的技术，应用在化学仪器和方法、植物学设备和方法、药物组合等方向，能够解决败血症死亡率增长等问题

Inactive Publication Date: 2006-06-14
GENENTECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] However, despite significant advances in the treatment of serious infections over the past few decades, sepsis incidence and mortality attributable to sepsis continue to increase

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example

[0072] The present invention may be further illustrated by the following examples of preferred embodiments of the invention, but it should be understood that these examples are provided for illustrative purposes only and are not intended to limit the scope of the invention unless otherwise specified.

[0073] Materials and Methods

[0074] Equipment: All equipment and solutions used were endotoxin-free according to the information provided by the manufacturer. Use polypropylene tubes for low background activation of complement.

[0075] Reagents: Sterile phosphate buffered saline (PBS) was purchased from Life Technologies (Paisley, UK) and Lepirudin (Refludan(R)) was purchased from Hoechst (Frankfurt am Main, Germany). Opsonized E. coli (1 x 10 9 bacteria / mL) were purchased from ORPEGEN Pharma (Heidelberg, Germany); the total endotoxin concentration in the E. coli suspension was 7 μg / mL when analyzed using the limulus amebocyte lysate assay . Mouse anti-human C5 / C5a mAb 13...

example 1

[0077] Complement activation induced by Escherichia coli but not LPS in a human whole blood inflammation model

[0078] This study used a human whole blood model as previously detailed in (Mollnes TE et al., Blood 2002; 100:1869-1877). Blood was collected from healthy volunteers and anticoagulated with lepirudin. Lepirudin has not been tested to interfere with complement activation. Escherichia coli (1×10 8 / mL), Escherichia coli (1×10 8 / mL) and LPS (0.5μg / mL) on complement activation. CVF (5 U / mL) was used as a control for fluid phase complement activation. All incubations were performed at 37°C. Plasma terminal sC5b-9 complex (TCC) formed by complement activation was measured by enzyme-linked immunoassay (ELISA) as detailed in (Mollnes TE et al., Scand. J. Immunol. 1985; 22:197-202). Narrator. In this assay, mAbs specific for TCC are coated on the surface of each well in a microtiter plate. Following incubation of samples, immobilized TCCs were detected by biotinyla...

example 2

[0083] Different activation pathways in granulocytes and monocytes exposed to Escherichia coli or LPS

[0084] The whole blood system described in Example 1 was also used to study the activation of granulocytes and monocytes by E. coli (via formation of C5a via complement activation) and LPS (via activation of the CD14 pathway). The upregulation of CD11b was used as an indicator of the activation of granulocytes and monocytes. Blood samples were mixed with anti-C5 / C5a mAb137-26, anti-CD14 18D11 F(ab′) 2 , mAb 137-26 and the combination of anti-CD14 18D11 F(ab')2 or PBS were pre-incubated for 4 minutes. Escherichia coli (1 × 10 7 bacteria / mL) or sonicated E. coli (1×10 7 bacteria / mL), LPS (0.5 μg / mL) or CVF (5 U / mL). Use PBS instead as a negative control. Baseline samples were processed just prior to addition of activator. After incubation at 37°C for 10 minutes, 100 μL of blood was used for flow cytometric analysis. Whole blood samples were fixed with paraformaldehyde a...

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Abstract

The present invention relates to a method for preventing or treating sepsis by co-administering to a patient a sepsis preventing or treating amount of one or more complement inhibitors and a sepsis preventing or treating amount of one or more CD14 pathway inhibitors. The complement inhibitor is preferably an antibody that binds to and inhibits a complement protein such as C5a, and the CD14 pathway inhibitor is preferably an antibody that binds to and inhibits components of the CD14 pathway such as CD14 and LPS.

Description

technical field [0001] The present invention generally relates to methods and compositions for the prevention and treatment of sepsis, and in particular, the present invention relates to the use of a combination of a complement inhibitor and a CD14 pathway inhibitor in the prevention or treatment of sepsis. Background technique [0002] complement [0003] The immune system protects the body from pathogenic bacteria, viruses, parasites and other harmful organisms. The immune system is divided into two parts: the humoral system and the cellular system. In general, the humoral system includes the complement system and the production of antibodies that defend against pathogens. The complement system, or simply complement, involves the production of proteins that assist antibodies in host defense. Complement is a group of proteins that includes at least 30 surface-bound soluble proteins. The activity of some soluble proteins was destroyed by heati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N37/18A61KA61K38/00C07K16/18C07K16/28
CPCC07K16/18C07K16/2896A61P31/00A61P31/04A61P37/04A61P43/00A61P7/00
Inventor 丰锡中汤姆·埃里克·莫尔内斯
Owner GENENTECH INC
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