Title:  Enhanced circulation effector composition and method

United States Patent:  6,326,353

Assignee:  Sequus Pharmaceuticals, Inc. (Menlo Park, CA)

Filed:  March 23, 1993

A liposome composition comprising small, surface-bound effector molecules is disclosed. The liposomes have a surface layer of hydrophilic polymer chains, for enhanced circulation time in the bloodstream. The effector molecules are attached to the distal ends of the polymer chains. In one embodiment, the effector is polymyxin B, for treatment of septic shock.

SUMMARY OF THE INVENTION

The invention includes, in one aspect, a method of treating a subject by parenteral administration of a polypeptide or polysaccharide effector which is rapidly removed from the bloodstream by renal clearance in free form. The method includes parenterally administering to the subject, a liposome composition containing liposomes having an outer layer of polymer chains and the effector covalently attached to the distal ends of said chains. A preferred polymer is polyethylene glycol with chain lengths between about 1,000 and 10,000 daltons molecular weight.

Preferred effectors include:

(a) an antibody F_ab fragment specific against a blood-circulating pathogen, for use in treating the subject for infection by the pathogen;

(b) a CD4 glycoprotein, for use in treating the subject for infection by human immunodeficiency virus (HIV);

(c) a cytokine or cellular growth factor, for use in stimulating an immune response in the subject;

(d) a mono or polysaccharide, such as sialyl Lewis^x, which binds to endothelial leukocyte adhesion molecule (ELAM), for use in treating a vascular inflammation related to neutrophil recruitment into sites of inflammation;

(e) IL-1 inhibitor or IL-1RA, for treating the subject to achieve immune-response suppression;

(f) polymyxin B, or polymyxin B decapeptide, for treating the subject for septic shock; and

(g) a peptide hormone, for treating diseases subject to peptide hormone control.

In one specific embodiment, the invention includes a method of preventing progression of gram-negative bacteremia to septic shock and a method of treating acute septic shock by administering to a subject, a liposome composition containing liposomes having an outer layer of polyethylene glycol (PEG) chains and polymyxin B attached to the distal ends of the polymer chains.

In another aspect, the invention includes a composition of liposomes, each having an outer layer of polymer chains, typically polyethylene glycol chains, and one of the above effectors (a)-(g) attached to the distal ends of the chains.

Claim 1 of 4 Claims

It is claimed:

1. In a method of treating a subject for septic shock by parenteral administration of polymyxin B, the improvement comprising

parenterally administering to the subject, a liposome composition containing liposomes having an outer layer of polyethylene glycol chains and said polymyxin B covalently attached to the distal ends of said chains.

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