Compositions and methods for inhibiting the biological activity of soluble biomolecules
The disclosure provides, among other things, compositions that bind to and inhibit the biological activity of soluble biomolecules, as well as pharmaceutical compositions thereof. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful.
1. A particle having at least one surface and an agent immobilized on the surface, wherein:
the agent selectively binds to a target that is a first member of a specific binding pair;
binding of the target to the particle inhibits the interaction of the target with a second member of the specific binding pair;
the target is a soluble biomolecule;
the soluble biomolecule is a form of a cell surface receptor protein expressed by a cancer cell; and
the agent is disposed on a surface of the particle such that it is sterically inhibited from binding or activating the cell surface receptor protein on the surface of a cell.
2. The particle of claim 1 , wherein the particle is shaped and sized to circulate in the vasculature of a subject.
3. The particle of claim 2 , wherein the longest dimension of the particle is no greater than about 1 μm.
4. The particle of claim 3 , wherein the smallest dimension of the particle is at least about 300 nm.
5. The particle of claim 1 , further comprising a plurality of coating molecules.
6. The particle of claim 5 , wherein:
the particle comprises an interior surface and an exterior surface;
the agent is immobilized on the interior surface and the exterior surface;
the plurality of coating molecules are bound to the exterior surface; and
the coating molecules inhibit interactions between the agent and molecules on a cell surface.
7. The particle of claim 5 , wherein the plurality of coating molecules increases the clearance of the particle in vivo.
8. The particle of claim 7 , wherein the plurality of coating molecules increases the clearance of the particle by phagocytosis, renal clearance, or hepatobiliary clearance.
9. The particle of claim 5 , wherein the plurality of coating molecules decreases the clearance of the particle in vivo.
10. The particle of claim 9 , wherein the plurality of coating molecules is biodegradable.
11. The particle of claim 10 , wherein the plurality of coating molecules comprises a biodegradable polymer.
12. The particle of claim 1 , wherein the particle comprises two intersecting ridges extending from the surface of the particle, and the ridges are sized and oriented to inhibit: (i) the agent immobilized on the surface of the particle from binding or activating a cell surface receptor protein and/or (ii) when the target is bound to the agent, the interaction of the target and a second member of a specific binding pair of which the target is the first member.
13. The particle of claim 1 , wherein the agent is a ligand of a cell surface receptor protein.
14. The particle of claim 1 , wherein the agent is a natural ligand of a cell surface receptor protein.
15. The particle of claim 1 , wherein the cell surface receptor protein is a protein shed by the cancer cell as a soluble form of the cell surface receptor protein.
16. The particle of claim 1 , wherein the cell surface receptor protein, when activated on a cell surface, induces apoptosis.
17. The particle of claim 1 , wherein the cell surface receptor protein is a tumor necrosis factor receptor (TNFR) protein.
18. The particle of claim 1 , wherein the cell surface receptor protein is a Fas receptor protein.
19. The particle of claim 1 , wherein the cell surface receptor protein is a TNF-related apoptosis-inducing ligand receptor (TRAILR) protein, 4-1BB receptor protein, CD30 protein, EDA receptor protein, HVEM protein, lymphotoxin beta receptor protein, DR3 protein, or TWEAK receptor protein.
20. The particle of claim 1 , wherein the cell surface receptor protein is an interleukin receptor protein.
21. The particle of claim 20 , wherein the interleukin receptor protein is an IL-2 receptor protein.
22. The particle of claim 20 , wherein the agent is an interleukin protein or variant thereof.
23. The particle of claim 20 , wherein the interleukin protein is an IL-2 protein.
24. The particle of claim 1 , wherein the agent comprises a tumor necrosis factor (TNF) family ligand or a variant thereof.
25. The particle of claim 24 , wherein the TNF family ligand is TNFα.
26. The particle of claim 24 , wherein the TNF family ligand is selected from Fas ligand, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TLA1, TWEAK, TNFβ, and TRAIL.
27. The particle of claim 1 , wherein the surface is oriented such that the agent has a reduced ability to bind to a molecule on the surface of a cell.
28. The particle of claim 1 , wherein the agent has a reduced ability to activate a cell surface receptor protein, relative to the ability of a natural ligand of the cell surface receptor protein.
29. The particle of claim 28 , wherein the agent does not activate the cell surface receptor protein.
30. The particle of any one of the preceding claims, wherein the agent is a small molecule, a macrocycle compound, a polypeptide, a protein, a peptide, a peptidomimetic compound, a nucleic acid, or a nucleic acid analog.