Enhanced ciruclation effector composition and method

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes

Reexamination Certificate

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C530S319000, C530S350000

Reexamination Certificate

active

06180134

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an enhanced-circulation effector composition and method for treating a subject with small effector molecules which are normally subject to rapid renal clearance from the bloodstream.
References
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BACKGROUND OF THE INVENTION
A number of emerging or current therapies involve intravenous injection of small (less than 50 Kdaltons) protein, polypeptide or polysaccharide effectors. Such effectors can include F
ab
antibody fragments for use in active immunity, cytokines and cellular growth factors for stimulating immunological inflammatory responses, hormones, and polysaccharides, which are capable of interacting with endothelial cell receptors to competitively block neutrophil binding to activated endothelial cells lining the blood vessel (Katre, et al.; Philips, et al.; Waldmann).
Other small polypeptide effectors have been pro-posed for use in blocking viral infection of target cells in the blood, such as a CD4+ glycopeptide which is effective to inhibit binding of human immunodeficiency virus (HIV) to CD4+ cells (Capon and Ward; Janeway).
Polymyxin B, a small basic peptide which is rapidly excreted by the kidneys, is known to react with and neutralize gram-negative bacterial endotoxins, specifically
E. coli
0111:B4 liposaccharide (LPS) (Baldwin, et al.). It is not often administered parenterally as a treatment for septic shock syndrome, because high doses of polymyxin B are required for effective treatment. High doses can be fatal, due to renal toxicity, making advanced stages of septic shock difficult to treat.
The problem of rapid renal clearance observed with polymyxin B is also applicable to other small peptides, such as those discussed above, which have been used for parenteral treatment of disease. In general, circulating proteins which are smaller than about 50-60 Kdaltons will be cleared by the kidneys with a lifetime of less than 1-2 hours.
In some cases, peptide molecular weight can be increased above the threshold 50-60 Kdalton size by derivatizing the peptide with biologically compatible polymers, such as polyethyleneglycol (PEG) (e.g., U.S. Pat. No. 4,179,337). However, this strategy may not always be effective for small effectors, e.g., those with molecular weights less than about 5-10 Kdalton. Moreover, derivatizing a polypeptide with a plurality of PEG chains may destroy or reduce the polypeptide activity, and/or mask key activity sites of the polypeptide.
SUMMARY OF THE INVENTION
The invention includes, in one aspect, a liposome composition for use in treating a subject with a polypeptide or polysaccharide effector which is effective as a pharmacological agent when circulating in free form in the bloodstream, but which is rapidly removed from the bloodstream by renal clearance in free form. The composition includes liposomes having an outer surface layer of polyethylene glycol chains and the effector covalently attached to the distal ends of the chains. A preferred polymer is polyethylene glycol having a molecular weight between about 1,000 and 10,000 daltons.
Preferred effectors include:
(a) an antibody F
ab
fragment having neutralizing activity against a given pathogen present in the bloodstream, 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 a cellular growth factor, for use in stimulating an immune response in the subject;
(d) a polysaccharide which binds to endothelial leukocyte adhesion molecule (ELAM), for use in treating inflammation related to neutrophil recruitment and tissue infiltration;
(e) IL-1 inhibitor or IL-IRA, for treating a subject to achieve immune-response suppression;
(f) polymyxin B or polymyxin B decapeptide, for treating the subject for septic shock;
(g) a peptide hormone, for treating a subject to regulate cellular growth; and
(h) a peptide, for inhibiting a ligand-receptor cell-binding event.
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 liposome composition for use in preventing rapid removal from the bloodstream of a polypeptide or polysaccharide effector by renal clearance. The composition includes liposomes having an outer layer of polyethylene glycol chains, and attached to the distal ends of the chains, is one of the above effectors (a)-(h).
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.


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