Methods and compositions for treating secondary tissue damage and other inflammatory conditions and disorders

• US 20110160126A1
• Filed: 02/24/2011
• Published: 06/30/2011
• Est. Priority Date: 07/22/1998
• Status: Abandoned Application

• Current Assignee: Osprey Pharmaceuticals USA, Inc. (Osprey Pharmaceuticals Limited)
• Original Assignee: Osprey Pharmaceuticals USA, Inc. (Osprey Pharmaceuticals Limited)
• Inventors: Coggins, Philip J., McDonald, John R.
• Application Number:
  US12/932,472
• Publication Number:
  US 20110160126A1
• Time in Patent Office: Days
• US Class Current: 514/3.7
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/6415 Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
• CPC Class Codes: A61K 47/642 the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
• CPC Class Codes: A61K 47/6425 the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical
• CPC Class Codes: C07K 14/415 from plants
• CPC Class Codes: C07K 14/521 Chemokines
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 17/00 Carrier-bound or immobilised peptides carrier-bound or immobilised enzymes C12N11/00; Preparation thereof
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C07K 2319/55 containing a fusion with a toxin, e.g. diphteria toxin

Abstract

Methods for treatment of diseases, including human immunideficiency virus infection, are provided. The disease are treated by administering conjugates containing as a ligand a chemokine receptor targeting agents, such as a chemokine, and a targeted agent, such as a toxin.

Claims

1. A conjugate, comprising a targeted agent and a chemokine or a portion thereof, wherein:

the conjugate binds to a chemokine receptor resulting in internalization of the targeted agent in cells bearing the receptor; and

the chemokine receptor is a virally-encoded chemokine receptor.

2. The conjugate of claim 1, wherein the chemokine and targeted agent are linked directly.

3. The conjugate of claim 1, wherein the chemokine and targeted agent are joined via a linker.

4. The conjugate of claim 3, wherein the linker comprises a peptide or a polypeptide or is a chemical linker.

5. The conjugate of claim 4, wherein the linker is a peptide or an amino acid.

6. The conjugate of claim 1, wherein the targeted agent is a toxin, and the toxin is a ribosome inactivating protein, a bacterial toxin or a fragment thereof that retains the ribosome inactivating or toxin activity.

7. The conjugate of claim 4, wherein the linker is a chemical linker selected among N-succinimidyl(4-iodoacetyl)-aminobenzoate, sulfosuccinimydil(4-iodoacetyl)-aminobenzoate, 4-succinimidyl-oxycarbonyl-α

-(2-pyridyldithio)toluene, sulfosuccinimidyl-6-(α

-methyl-α

-(pyridyldithiol)-toluamido)hexanoate, N-succinimidyl-3-(-2-pyridyldithio)-proprionate, succinimidyl 6(3(-(-2-pyridyldithio)-proprionamido)hexanoate, sulfosuccinimidyl 6(3(-(-2-pyridyldithio)-propionamido)hexanoate, 3-(2-pyridyldithio)-propionyl hydrazide, Ellman'"'"'s reagent, dichlorotriazinic acid, and S-(2-thiopyridyl)-L-cysteine.

8. The conjugate of claim 1, wherein the targeted agent is a toxin.

9. The conjugate of claim 8, wherein the toxin is a polypeptide.

10. The conjugate of claim 9, wherein the toxin is selected from among bacterial, plant, insect, snake and spider toxins.

11. The conjugate of claim 10, wherein the toxin is a ribosome inactivating protein (RIP).

12. The conjugate of claim 10, wherein the toxin is a bacterial toxin selected from among Pseudomonas exotoxin, Diphtheria toxins, shiga toxin, shiga-like toxins, catalytic subunits thereof, and toxic fragments thereof.

13. The conjugate of claim 1, wherein the cells bearing the virally-encoded receptor are immune effector cells.

14. The conjugate of claim 13, wherein immune effector cells are leukocytes.

15. A nucleic acid molecule, comprising a sequence of nucleotides encoding a conjugate of claim 1.

16. A plasmid, comprising the nucleic acid molecule of claim 15.

17. A host cell, comprising the plasmid of claim 16.

18. A method for inhibiting proliferation of virally infected cells, comprising administering a conjugate of claim 1 to an animal infected with a virus, wherein the targeted agent is a toxin.

19. The method of claim 18, wherein the infected cells are immune effector cells.

20. The method of claim 19, wherein the infected cells are leukocytes.

21. The method of claim 1, wherein the chemokine is selected from among IL-8, GCP-2, GRO-α

, GRO-β

, GRP-γ

, ENA-78, PBP, CTAP III, NAP-2, LAPF-4, MIG, IP-10, SDF-1α

, SDF-1β

, SDF-2, MCP-1, MCP-2, MCP-3, MCP-4, MCP-5, MIP-1α

, MIP-1β

, MIP-1γ

, MIP-2, MIP-2a, MIP-3α

, MIP-3β

, MIP-4, MIP-5, MDC, HCC-1, LD78β

, eotaxin-1, eotaxin-2, I-309, SCYA17, TARC, RANTES, DC-CK-1, lymphotactin and fractalkine.