Compositions for neutralization of lipopolysaccharides

• US 5,928,624 A
• Filed: 12/16/1996
• Issued: 07/27/1999
• Est. Priority Date: 06/14/1994
• Status: Expired due to Fees

• Current Assignee: Rockefeller University
• Original Assignee: Rockefeller University
• Inventors: Wurfel, Mark M., Hailman, Peter Eric, Wright, Samuel D.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/750,697
• Time in Patent Office: 953 Days
• Field of Search: 424/9.1, 436/503, 436/501, 436/519, 436/548, 436/71-811, 435/7.92
• US Class Current: 424/9.1
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1275 Lipoproteins; Chylomicrons; Artificial HDL, LDL, VLDL, protein-free species thereof; Precursors thereof
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: G01N 2333/5412 IL-6
• CPC Class Codes: G01N 2400/50 Lipopolysaccharides; LPS
• CPC Class Codes: G01N 33/92 involving lipids, e.g. cholesterol , lipoproteins, or their receptors steroid hormones G01N33/743
• CPC Class Codes: Y10S 436/811 Test for named disease, body condition or organ function

Abstract

The present invention relates to compositions and methods for neutralizing lipopolysaccharide, and treatment of gram-negative sepsis based thereon. Accordingly, the invention is directed to a composition of homogeneous particles comprising phospholipids and a lipid exchange protein, such as phospholipid transfer protein or LPS binding protein. The lipid exchange protein is characterized by being capable of faciliting an exchange of lipopolysaccharide into the particles. In a specific embodiment, exemplified herein, the lipid particles are high density lipoprotein particles comprising apolipoprotein A-I (apo A-I), a phospholipid, and cholesterol or a lipid bilayer binding derivative thereof. In a specific example, the phospholipid is phosphatidylcholine (PC). In a specific example, the ratio of phosphatidylcholine: cholesterol: apolipoprotein A-I is approximately 80:4:1. The level of LPS exchange protein activity in a sample from a patient provides a diagnostic, monitoring, or prognostic indicator for a subject with endotoxemia, gram-negative sepsis, or septic shock.

Claims

1. A method for monitoring or prognoisis of a subject suffering from gram-negative or endotoxin-mediated sepsis comprising:

a) measuring a first level of lipoprotein particles that contain a lipid exchange protein that is characterized by being capable of facilitating an exchange of lipopolysaccharide into the high density lipoprotein particles in a biological fluid of the subject, wherein the high density lipoprotein particles comprise lipoprotein A-I, and the lipid exchange protein is lipopolysaccharide binding protein;

b) measuring a second level of lipoprotein particles that contain a lipid exchange protein that is characterized by being capable of faciliating an exchange of lipopolysaccharide into the high density lipoprotein particles in the biological fluid of the subject, wherein the high density lipoprotein particles comprise lipoprotein A-I, and the lipid exchange protein is lipopolysaccharide binding protein; and

c) comparing the second level measured in step (h) with the first level measured in step (a), wherein an increase in the level indicates greater probability of a favorable outcome of the sepsis.

2. The method according to claim 1, wherein the lipid exchange proteins lipopolysaccharide binding protein.

3. The method according to claim 1, wherein the measuring comprises detecting a portion of lipoprotein particles containing apolipoprotein A-I that also contain lipopolysaccharide binding protein.

4. The method according to claim 1, wherein the measuring comprises detecting the capacity of plasma or serum from the subject to neutralize lipopolysaccharide activity.

5. The method according to claim 1, wherein the lipid exchange protein is phospholipid transfer protein.

6. The method of claim 1, wherein the biological fluid of the subject comprises plasma or serum.

7. The method of claim 3, wherein the detecting comprises measuring adherence of PMN to fibrinogen of the biological fluid, measuring induction of expression of cytokines in the biological fluid, or assaying the biological fluid by immunoassay.

8. The method of claim 7, wherein the immunoassay comprises antibodies reactive with a component of the high density lipoprotein containing lipoprotein A-I, or the lipopolysaccharide binding protein, or both.

9. The method of claim 7, wherein the cytokines comprise TNF or IL-1.

10. The method of claim 4, wherein the detecting comprises measuring the adherence of PMN to fibrinogen of the biological fluid, measuring the induction of expression of cytokines in the biological fluid, or assaying the biological fluid with an immunoassay.

11. The method of claim 10, wherein the immunoassay comprises antibodies reactive with a component of the lipoprotein or the lipopolysaccharide exchange protein, or both.

12. The method of claim 9, wherein the cytokines comprise TNF or IL-1.