Targeting of innate immune response to tumor site
The invention provides microparticles or nanoparticles for treatment of tumors comprising: (i) a targeting agent to the tumor or the tumor environment; and (ii) at least one inducer that stimulates a desired immune response in the tumor environment, leading to tumor apoptosis, wherein components (i) and (ii) are non-covalently or covalently attached to the surface of said microparticles or nanoparticles. The targeting agent is an agent that recognizes and binds to an antigen, a receptor or other molecules found on the surface of tumor cells or in the tumor environment and are preferably antibodies.
1. Microparticles or nanoparticles for treatment of tumors comprising:
a microparticulate or nanoparticulate core and, non-covalently or covalently attached to the surface thereof, the following components—
(i) a targeting agent to the tumor or the tumor environment, optionally biotinylated, selected from the group consisting of: (a) an antibody to a tumor-associated antigen or to a peptide of such an antigen found on the surface of tumor cells; (b) an antibody to a receptor found on the surface of tumor cells; (c) an antibody to an antigen in the tumor environment; and (d) a ligand to a receptor found on the surface of tumor cells, wherein said antibody of (a), (b) or (c) is a chimeric, human or humanized mAb; and
(ii) two or more inducers optionally biotinylated, that stimulates an innate immune response in the tumor environment, leading to tumor apoptosis, selected from the group consisting of mannose, mannan, lipopolysaccharide (LPS), a Toll-like Receptor (TLR) ligand, N-formyl-methionyl-leucyl-phenylalanine (fMLF or fMLP), Complement 3a (C3a), Complement 5a (C5a), and a C, CC, CXC or CX 3 C chemokine.
2. The microparticles or nanoparticles according to claim 1 , wherein said monoclonal antibody is selected from the group consisting of Alemtuzumab, Bevacizumab, Cetuximab, Edrecolomab, Epratuzumab, Gemtuzumab, Ibritumomab, Panitumumab, Rituximab, Tositumomab, Trastuzumab, and R1507.
3. The microparticles or nanoparticles according to claim 1 , wherein said TLR ligand is selected from the group consisting of: (i) a ligand to TLR1/2; (ii) a TLR2 ligand; (iii) a TLR3 ligand; (iv) a TLR4 ligand; (v) a TLR5 ligand; (vi) a TLR7 ligand; and (vii) a TLR 9 ligand.
4. The microparticles or nanoparticles according to claim 1 , wherein the two or more inducers are selected from the group consisting of optionally biotinylated LPS, mannose, mannan, or a TLR ligand.
5. The microparticles or nanoparticles according to claim 1 , comprising two inducers, wherein the first inducer is constantly released from the said microparticulate or nanoparticulate core and stimulates chemotaxis, and the second inducer is covalently bound to the surface of said microparticulate or nanoparticulate core.
6. The microparticles or nanoparticles according to claim 5 , wherein said first inducer is selected from the group consisting of fMLF, C3a, C5a, a C chemokine, a CC chemokine, a CXC chemokine and a CX 3 C chemokine.
7. The microparticles or nanoparticles according to claim 1 , wherein said microparticulate or nanoparticulate core is composed of an iron oxide, a synthetic polymer, a polysaccharide, or a protein, has a size from about 5 nm to about 100 micron, may be biodegradable, and may be coated with avidin or streptavidin for binding to biotinylated targeting agents or inducers, or have functional groups on the surface for covalent binding with targeting agents or inducers.
8. The microparticles or nanoparticles according to claim 7 , wherein the core is microparticles of the synthetic polymer, polystyrene, or iron oxide coated with avidin and wherein the attached targeting agent is biotinylated anti-HER2 monoclonal antibody and the attached inducer is biotinylated LPS.
9. The microparticles or nanoparticles according to claim 7 , wherein said synthetic polymer is polystyrene.
10. A pharmaceutical composition for treatment of tumors comprising microparticles or nanoparticles according to claim 1 .
11. The microparticles or nanoparticles of claim 1 , wherein the synthetic polymer is selected from the group consisting of polystyrene and copolymers thereof, polymethylmethacrylate, polyvinyltoluene, and polyamines.
12. A kit for treatment of malignant tumors comprising:
(i) a composition comprising microparticles or nanoparticles having a microparticulate or nanoparticulate core carrying (a) a targeting agent to the tumor or the tumor environment and (b) an agent A, which is a member of a pair of agents A-B that bind with high affinity to each other, wherein said targeting agent is selected from the group consisting of: (A) an antibody to a tumor-associated antigen or to a peptide of such an antigen found on the surface of tumor cells; (B) an antibody to a receptor found on the surface of tumor: (C) an antibody to an antigen in the tumor environment; and (D) a ligand to a receptor found on the surface of tumor cells, wherein said antibody of (A), (B) or (C) is a chimeric, human or humanized mAb;
(ii) a composition comprising microparticles or nanoparticles having a microparticulate or nanoparticulate core carrying (c) two or more inducers that stimulates an innate immune response in the tumor environment, selected from the group consisting of mannose, mannan, lipopolysaccharide (LPS), a Toll-like Receptor (TLR) ligand, N-formyl-methionyl-leucyl-phenylalanine fMLF or fMLP), Complement 3a (C3a), Complement 5a (C5a), and a C, CC, CXC or CX 3 C chemokine, and (d) the agent B of said pair of agents A-B; and
(iii) a leaflet with instructions for administration of composition (i) before composition (ii),
wherein the components of each of the compositions (i) and (ii) are non-covalently or covalently attached to the surface of said microparticulate or nanoparticulate cores.
13. The kit according to claim 12 , wherein the Toll-like Receptor (TLR) ligand is selected from the group consisting of: (i) a ligand to TLR1/2; (ii) a TLR2 ligand; (iii) a TLR3 ligand; (iv) a TLR4 ligand; (v) a TLR5 ligand; (vi) a TLR7 ligand; and (vii) a TLR 9 ligand.
14. The kit according to claim 12 , wherein the microparticulate or nanoparticulate cores are composed of an iron oxide, a synthetic polymer, a polysaccharide, or a protein, have a size from about 5 nm to about 100 micron, may be biodegradable, and may be coated with avidin or streptavidin for binding to biotinylated targeting agents or inducers, or have functional groups on the surface for covalent binding with targeting agents or inducers.
15. The kit according to claim 14 , wherein said synthetic polymer is polystyrene.
16. The kit according to claim 12 , wherein said chimeric, human or humanized monoclonal antibody is biotinylated and is selected from the group consisting of a humanized anti-HER2 mAb, Alemtuzumab, Bevacizumab, Cetuximab, Edrecolomab, Epratuzumab, Gemtuzumab, Ibritumomab, Panitumumab, Rituximab, Tositumomab, and R1507.
17. The kit of claim 12 , wherein the synthetic polymer is selected from the group consisting of polystyrene and copolymers thereof, polymethylmethacrylate, polyvinyltoluene, and polyamines.
18. A kit for treatment of malignant tumors comprising:
(i) a composition comprising microparticles or nanoparticles having a microparticulate or nanoparticulate core carrying (a) a targeting agent to the tumor or the tumor environment and (b) an agent A, which is a member of a pair of agents A-B that bind with high affinity to each other, wherein said targeting agent is selected from the group consisting of: (A) an antibody to a tumor-associated antigen or to a peptide of such an antigen found on the surface of tumor cells; (B) an antibody to a receptor found on the surface of tumor cells: (C) an antibody to an antigen in the tumor environment; and (D) a ligand to a receptor found on the surface of tumor cells, wherein said antibody of (A), (B) or (C) is a chimeric, human or humanized mAb;
(ii) a composition comprising microparticles or nanoparticles having a microparticulate or nanoparticulate core carrying (c) the agent B of said pair of agents A-B, and (d) an agent C, which is a member of a pair of agents C-D that bind with high affinity to each other;
(iii) a composition comprising microparticles or nanoparticles having a microparticulate or nanoparticulate core carrying the agent D of said pair of agents C-D; and
(iv) a leaflet with instructions for administration of sequential administration of compositions (i), (ii) and (iii), respectively,
wherein the components of each of the compositions (i), (ii) and (iii) are non-covalently or covalently attached to the surface of said microparticulate or nanoparticulate cores.
19. The kit according to claim 18 , wherein each of the pair of agents A-B and C-D that bind with high affinity to each other is different from each other and is selected from biotin-avidin or streptavidin, wherein the biotin is covalently linked to the targeting agent in the microparticles or nanoparticles of composition (i) and the avidin or streptavidin is present as coating of the microparticulate or nanoparticulate core of composition (ii); and an antigen-antibody to said antigen.
20. The kit according to claim 19 , wherein said antigen-antibody is selected from the group consisting of tetanus toxoid (TT) antigen—anti-TT antibody and BSA-anti-BSA antibody.