Methods and compositions for treating secondary tissue damage and other inflammatory conditions and disorders
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.
1 . A method of treatment of human immunideficiency virus (HIV) infection, comprising administering a conjugate to a human infected with an HIV, wherein:
the conjugate comprises a targeted agent and a chemokine receptor targeting agent;
the conjugate binds to a receptor resulting in internalization of the linked targeted agent in cells bearing the receptor; and
the receptor is selected from among CXCR4, CCR2b, CCR3, CCR5, CCR6, CCR8 and CX3CR1.
2 . A method of claim 1 , wherein:
the conjugate comprises the following components: (chemokine receptor targeting agent) n , (L) q and (targeted agent) m ;
L is a linker for linking the chemokine receptor targeting agent to a targeted agent;
the chemokine receptor targeting agent is a moiety that selectively binds a receptor selected from among CXCR4, CCR2b, CCR3, CCR5, CCR6, CCR8 and CX3CR1;
m and n, which are selected independently, are at least 1;
q is 0 or more as long as the resulting conjugate binds to the targeted receptor, is internalized and delivers the targeted agent; and
the resulting conjugate binds to a receptor selected from the group consisting of CXCR4, CCR2b, CCR3, CCR5, CCR6, CCR8 and CX3CR1, whereby the targeted agent(s) is internalized in a cell bearing the receptor.
3 . The method of claim 2 , wherein m and n, which are selected independently, are 1-6.
4 . The method of claim 2 , wherein q is 1, n is 1 and m is 1.
5 . The method of claim 1 , wherein the chemokine receptor targeting agent is a chemokine, an antibody that specifically binds to a chemokine receptor or a fragment of the chemokine or antibody, wherein the fragment binds to the receptor and internalizes the targeted agent, and the receptor is selected from the group consisting of CXCR4, CCR2b, CCR3, CCR5, CCR6, CCR8 and CX3CR1.
6 . The method of claim 1 , wherein the receptor is expressed on CD4+ cells.
7 . The method of claim 6 , wherein the CD4+ cells are infected with HIV.
8 . The method of claim 1 , wherein the receptor is expressed on mononuclear phagocytes (MNPs).
9 . The method of claim 1 , wherein the receptor targeting agent is selected from the group consisting of SDF-1α, SDF-1β, eotaxin and Regulated on Activation, Normal T cell Expressed and Secreted chemokine (RANTES).
10 . The method of claim 1 , wherein the targeted agent is a toxin or toxic fragment thereof, a nucleic acid molecule or a therapeutic protein.
11 . The method of claim 10 , wherein the cell toxin is a DNA cleaving agent.
12 . The method of claim 11 , wherein the DNA cleaving agent is selected from among anthraquinone-oligopyrrolcarboxamide, benzimidazole, leinamycin, dynemycin A, enediyne, endiyne quinone imines, 2,2r-bis(2-aminoethyl)-4-4′-bithiazole, epilliticine-salen.copper conjugates, and functional analogs or derivatives thereof.
13 . The method of claim 10 , wherein the toxin is an antimetabolite.
14 . The method of claim 13 , wherein the antimetabolite is selected from among of 5-fluorouracil, methotrexate, melphalan, daunomycin, doxorubicin, nitrogen mustard, mitomycin c, and functional analogs or derivatives thereof.
15 . The method of claim 10 , wherein the toxin is selected from among bacterial, plant, insect, snake and spider toxins.
16 . The method of claim 15 , wherein the cell toxin is selected from the group consisting of bacterial, plant, insect, snake and spider toxins.
17 . The method of claim 16 , wherein the cell toxin is a ribosome inactivating protein (RIP).
18 . The method of claim 17 , wherein the RIP is a type one RIP or a biologically functional fragment thereof.
19 . The method of claim 18 , wherein the type one RIP is selected from the group consisting of dianthin 30, dianthin 32, lychnin, saporin-1, saporin-2, saporin-3, saporin-4, saporin-5, saporin-6, saporin-7, saporin-8 and saporin-9, PAP, PAP II, PAP-R, PAP-S, PAP-C, mapalmin, dodecandrin, bryodin-L, bryodin, colicin-1, colicin-2, luffin-A, luffin-B, luffin-S, 19K-PSI, 15K-PSI, 9K-PSI, alpha-kirilowin, beta-kirilowin, gelonin, momordin, momordin-II, momordin-Ic, MAP-30, alpha-momorcharin, beta-momorcharin, trichosanthin, TAP-29, trichokirin, barley RIP, tritin, flax RIP, corn RIP, asparin-1, and asparin-2.
20 . The method of claim 17 , wherein the RIP is a type two RIP, the catalytic subunit thereof, or a biologically functional subunit or fragment thereof.
21 . The method of claim 20 , wherein the type two RIP is selected from the group consisting of volkensin, ricin, nigrin-CIP-29, abrin, vircumin, modeccin, ebulitin-α, ebulitin-β, ebultin-γ, and porrectin.
22 . The method of claim 15 , wherein the toxin is a bacterial toxin selected from among Pseudomonas exotoxin, Diphtheria toxin, shiga toxin, shiga-like toxins, catalytic subunits thereof, and fragments thereof that exhibit activity as a toxin.
23 . The method of claim 1 , wherein the chemokine receptor targeting agent and targeting agent are linked directly via a covalent or ionic linkage.
24 . The method of claim 1 , wherein the chemokine receptor targeting agent and targeting agent are joined via a linker.
25 . The method of claim 24 , wherein the linker is a polypeptide or is chemical linker.
26 . The method of 24 , wherein the chemical linker is a heterobi-functional cleavable cross-linker.
27 . The method of claim 26 , wherein the chemical linker is selected from among N-succinimidyl(4-iodoacetyl)-aminobenzoate, sulfosuccinimydil (4-iodoacetyl)-aminobenzoate, 4-succinimidyl-oxycarbonyl-a-(2-pyridyldithio)toluene, sulfosuccinimidyl-6-[a-methyl-a-(pyridyldithiol)-toluamido] hexanoate, N-succinimidyl-3-(-2-pyridyidithio)-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.
28 . The method of claim 24 , wherein the linker is a peptide or an amino acid.
29 . The method of claim 28 , wherein the peptide comprises between 1 and 60 amino acids.
30 . The method of claim 29 , wherein the linker is selected from among peptides that reduce steric hindrance between the targeted agent and chemokine receptor targeting agent, intracellular enzyme substrates, linkers that increase the flexibility of the conjugate, linkers that increase the solubility of the conjugate, linkers that increase the serum stability of the conjugate, photocleavable linkers and acid cleavable linkers. amino acid residues.
31 . The method of claim 1 , wherein the chemokine receptor targeting agent is a monoclonal antibody, or an antigen-specific fragment thereof.
32 . The method of claim 1 , wherein that the receptor is CXCR4 and the receptor targeting agent is SDF-1α or SDF-1β.
33 . The method of claim 1 , wherein the receptor is CCR2b and the receptor targeting agent is selected from the group consisting of MCP-1, MCP-2, MCP-3 and MCP-4.
34 . The method of claim 1 , wherein the receptor is CCR3 and the receptor targeting agent is selected from the group consisting of Eotaxin-1, Eotaxin-2, Regulated on Activation, Normal T cell Expressed and Secreted chemokine (RANTES) and MIP-5.
35 . The method of claim 1 , wherein the receptor is CCR5 and the receptor targeting agent is selected from the group consisting of RANTES, MIP-1α and MIP-1β.
36 . The method of claim 1 , wherein the receptor targeting agent is MIP-3α.
37 . The method of claim 1 , wherein the receptor is CCR8 and the receptor targeting agent is I-309 or a MIP-1.
38 . The method conjugate of claim 1 , wherein the receptor is CXC3R1 and the receptor targeting agent is fractalkine.
39 . The method of claim 1 , wherein the receptor is expressed on cells selected from the group consisting of mononuclear phagocytes, microglia, T-lymphocytes, natural-killer cells, neutrophils, dendritic cells, B-lymphocytes, eosinophils and basophils.