Antigen-processing cell-targeted conjugates

• US 5,898,033 A
• Filed: 12/19/1997
• Issued: 04/27/1999
• Est. Priority Date: 06/07/1995
• Status: Expired due to Term

• Current Assignee: Joel K. Swadesh, Martin Sevoian
• Original Assignee: Joel K. Swadesh, Martin Sevoian
• Inventors: Sevoian, Martin, Swadesh, Joel K.
• Primary Examiner(s): MacMillan, Keith D.
• Application Number:
  US08/994,334
• Time in Patent Office: 494 Days
• Field of Search: 514/616, 514/570, 514/224.2, 514/825, 514/824, 528/328
• US Class Current: 514/224.2
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

An anti-inflammatory conjugate including a polyamino acid backbone, a non-steroidal anti-inflammatory agent, and a moiety linking the anti-inflammatory agent to the backbone, wherein the polyamino acid backbone has a molecular weight greater than 250 kD.

Claims

1. An anti-inflammatory, non-immunogenic conjugate comprising:

a polyamino acid backbone;

a multiplicity of molecules of a non-steroidal anti-inflammatory agent; and

a multiplicity of moieties linking said molecules to said backbone, wherein said polyamino acid backbone has an average molecular weight greater than 250 kD, said polyamino acid backbone comprises greater than 80 percent poly-γ

-glutamic acid, said moieties link said molecules of anti-inflammatory agent to said backbone via α

-carboxylate groups of the poly-γ

-glutamic acid, and said conjugate is preferentially internalized by antigen-processing cells compared to said agent absent the backbone.

2. A conjugate of claim 1, wherein said anti-inflammatory agent is 15-deoxyspergualin, spergualin, piroxicam, or ibuprofen.

3. A conjugate of claim 1, wherein said moiety linking said anti-inflammatory agent to said backbone is an amide bond, an ester bond, or a thioester bond.

4. A conjugate of claim 1, wherein said polyamino acid backbone has a molecular weight between 500 kD and 1500 kD.

14. A method of treating an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a conjugate of claim 1.

15. A method of claim 14, wherein said disease is rheumatoid arthritis, uveitis, psoriasis, type I diabetes, silicosis, polymyositis, coronary heart disease, pernicious anemia, pemphigus vulgaris, encephalitis, ulcerative colitis, Sjogren'"'"'s syndrome, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, or emphysema.

5. An anti-inflammatory, non-immunogenic conjugate comprising a derivatized polyamino acid of the formula:

space="preserve" listing-type="equation">H--{--NH--C.sup.* H (--X.sup.m M.sup.m Y.sup.m)--(CH.sub.2) .sub.n --(C═

O)--}.sub.p --OH

wherein each X^m independently is C_1-12 alkylene or deleted;

each M^m independently is (C═

O)--O, (C═

O)--NH, or (C═

O )--S, wherein the carbon atom of M^m is bonded either to X^m or, when X^m is deleted, to C^* ;

each Y^m independently is H, C_1-12 alkyl, --(CH₂)_a --O--(CH₂)_b H, or a nonsteroidal anti-inflammatory agent, wherein at least one Y^m is a nonsteroidal anti-inflammatory agent, and each of a and b independently is an integer between 0 and 12; and

p is an integer between 1,900 and 15,000, m is an integer ranging between 1 and p;

each n is independently an integer between 1 and 5;

said polyamino acid backbone has molecular weight greater than 250 kD; and

said conjugate is preferentiallv internalized by anti-processing cells compared to said agent absent the backbone.

6. A conjugate of claim 5, wherein each M^m independently is (C═

O)--O or (C═

O)--NH.

7. A conjugate of claim 5, wherein Y^m is 15-deoxyspergualin, spergualin, piroxicam, or ibuprofen.

8. A conjugate of claim 5, wherein n is 2.

9. A conjugate of claim 5, wherein X^m is deleted.

10. A conjugate of claim 5, wherein the stereochemistry of each chiral carbon C^* is L.

11. A conjugate of claim 5, wherein the stereochemistry of each chiral carbon C^* is D.

12. A conjugate of claim 5, wherein p is between 4,000 and 13,000.

13. A conjugate of claim 5, wherein said polyamino acid backbone has a molecular weight between 500 kD and 1500 kD.

18. A method of targeting an anti-inflammatory agent to a circulating antigen-processing cell in a mammal, comprising

obtaining an anti-inflammatory conjugate of claim 5;

and

injecting an amount of said anti-inflammatory conjugate into the mammal, thereby delivering an effective amount of said anti-inflammatory agent to a vascularly circulating antigen-processing cell in the mammal.

16. A method of targeting an anti-inflammatory agent to a circulating antigen-processing cell in a mammal, comprising

obtaining an anti-inflammatory conjugate comprising a polyamino acid backbone, an anti-inflammatory agent, and a moiety linking said anti-inflammatory agent to said backbone, wherein said polyamino acid backbone has a molecular weight greater than 250 kD;

and

injecting an amount of said anti-inflammatory conjugate into the mammal, thereby delivering an effective amount of said anti-inflammatory agent to a circulating antigen-processing cell in the mammal.

17. A method of claim 16, wherein said polyamino acid backbone is a poly-γ

-glutamic acid backbone.