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 method of treating cancer in a subject in need thereof, comprising:
administering to the subject a composition comprising a particle, wherein:
the particle comprises an agent that selectively binds to a target biomolecule;
the particle comprises a coating that reduces interactions between the agent and a cell; and
the particle is shaped and sized to circulate in the vasculature of the subject;
thereby scavenging the target biomolecule.
2 . The method of claim 1 , wherein the coating sterically inhibits interactions between the agent and a cell.
3 . The method of claim 1 , wherein the coating inhibits interactions between the agent and a target biomolecule expressed on a cell surface.
4 . The method of claim 1 , wherein the cancer is selected from lung cancer, breast cancer, colon cancer, pancreatic cancer, renal cancer, stomach cancer, liver cancer, bone cancer, hematological cancer, neural tissue cancer, melanoma, thyroid cancer, ovarian cancer, testicular cancer, prostate cancer, cervical cancer, vaginal cancer, and bladder cancer.
5 . The method of claim 1 , wherein the cancer is metastatic cancer.
6 . The method of claim 1 , wherein the particle has a surface and the agent is bound to the surface.
7 . The method of claim 1 , wherein the agent comprises
(i) an antibody or a target biomolecule-binding fragment of an antibody, wherein the target biomolecule-binding fragment is selected from a Fab fragment, a F (ab) 2 fragment, an scFv fragment, and a domain antibody,
(ii) a non-antibody scaffold protein,
(iii) a cytokine,
(iv) a tumor necrosis factor (TNF) family ligand, or
(v) a nucleic acid, an aptamer, or a nucleic acid analog.
8 . The method of claim 1 , wherein the agent comprises a TNF family ligand and the TNF family ligand is selected from TNFα, TNFβ, Fas ligand, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, ectodysplasin-A1 (EDA-A1), tumor necrosis factor superfamily member 14 (LIGHT), tumor necrosis factor superfamily member 15 (TLA1), TNF-related weak inducer of apoptosis (TWEAK), and targeting TNF-related apoptosis-inducing ligand (TRAIL).
9 . The method of claim 1 , wherein the agent comprises
(i) a target biomolecule-binding fragment of an antibody, and the target biomolecule-binding fragment is selected from a Fab fragment, a F (ab) 2 fragment, an scFv fragment, and a domain antibody, or
(ii) an aptamer.
10 . The method of claim 1 , wherein the target biomolecule is a soluble biomolecule.
11 . The method of claim 1 , wherein the target biomolecule is selected from a soluble cell membrane protein, cytokine, soluble cytokine receptor, matrix metallopeptidase (MMP), and immune checkpoint protein.
12 . The method of claim 1 , wherein the target biomolecule is selected from a soluble form of a tumor necrosis factor receptor (sTNFR) and a soluble interleukin receptor (SILR).
13 . The method of claim 1 , wherein the target biomolecule is sTNFR1 or sTNFR2.
14 . The method of claim 1 , wherein the target biomolecule is a soluble form of PD-L1.
15 . The method of claim 1 , wherein the target biomolecule is selected from sIL-1R, SIL-2R, SIL-5R, SIL-6R, SIL-8R, CXCL8, CXCL1, soluble TRAIL receptor, soluble TWEAK receptor, soluble 4-1BB receptor, CD30 protein, soluble EDA receptor, HVEM protein, soluble Fas receptor, soluble Fas ligand, soluble lymphotoxin beta receptor, soluble decoy receptor-3, soluble death receptor-3, soluble death receptor-4, and soluble death receptor-5.
16 . The method of claim 1 , wherein the target biomolecule is selected from CD80/B7-1, CD86/B7-2, and indoleamine 2,3-dioxygenase.
17 . The method of claim 11 , wherein the MMP is selected from MMP1, MMP2, MMP3, MMP9, MMP10, and MMP12.
18 . The method of claim 1 , wherein the coating comprises at least one diblock copolymer or triblock copolymer, wherein the diblock copolymer or the triblock copolymer comprises a hydrophilic moiety.
19 . The method of claim 18 , wherein the hydrophilic moiety comprises a polyethylene glycol (PEG) moiety.
20 . The method of claim 1 , wherein the coating comprises a diblock copolymer selected from polycaprolactone-PEG (PCL-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), poly(lactic acid-co-PEG) (PLA-PEG), and poly(methyl methacrylate)-PEG (PMMA-PEG), or a triblock copolymer poly(ethylene glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol) (PEG-PLGA-PEG).
21 . The method of claim 1 , wherein the coating comprises a polymer selected from a polyether, poly-alpha hydroxy acid, poly-beta hydroxy acid, poly(amino acid), sugar, lipid, polyvinyl alcohol, polyester, polyorthoester, polyamidoester, polyphosphoester, and urethane, or a combination thereof.
22 . The method of claim 21 , wherein the polymer comprises polyethylene glycol (PEG), polyglutamic acid, polyglycolic acid (PGA), polylactic acid (PLA), polylactate, poly(lactic-co-glycolic acid) (PLGA), polyvinyl acetate (PVA), polyhydroxybutyrate, or polyhydroxyvalerate, or a combination thereof.
23 . The method of claim 1 , wherein the cancer comprises cancer cells that shed a soluble form of a cell surface receptor protein.
24 . The method of claim 23 , wherein the cell surface receptor protein, when activated, induces apoptosis.
25 . The method of claim 23 , wherein the soluble form of the cell surface receptor protein is a soluble form of a cytokine receptor.
26 . The method of claim 23 , wherein the soluble form of the cell surface receptor protein is a soluble form of an interleukin receptor protein.
27 . The method of claim 25 , wherein the soluble form of the cytokine receptor is a soluble form of TNF receptor or IL-2 receptor.
28 . The method of claim 25 , wherein the soluble form of the cytokine receptor is sTNFR1.
29 . The method of claim 25 , wherein the soluble form of the cytokine receptor is sTNFR2.
30 . The method of claim 25 , wherein the soluble form of the cytokine receptor is a soluble form of TRAIL receptor.
31 . The method of claim 23 , wherein the soluble form of the cell surface receptor protein is a soluble form of Fas receptor protein, 4-1BB receptor protein, CD30 protein, EDA receptor protein, HVEM protein, lymphotoxin beta receptor protein, or TWEAK receptor protein.
32 . The method of claim 1 , wherein the cancer comprises cancer cells that shed a matrix metalloproteinase.
33 . The method of claim 32 , wherein the matrix metalloproteinase is selected from MMP1, MMP2, MMP3, MMP9, MMP10, and MMP12.
34 . The method of claim 1 , wherein the cancer comprises cancer cells that shed CXCL1.