SELECTIVE DRUG DELIVERY COMPOSITIONS AND METHODS OF USE
Described herein are methods and compositions for intracellular delivery of therapeutic molecules. Disclosed herein are selective delivery conjugate comprising a targeting ligand conjugated to a selective delivery molecule (a) an acidic sequence (portion of A) which is effective to inhibit or prevent the uptake into cells or tissue retention, (b) a molecular transport or retention sequence (portion of B), and (c) a linker between portion of A and portion of B, and (d) at least one cargo moiety. Also, described are selective delivery molecules comprising a second linker comprising an intracellular cleavage site and optionally a self-immolative cleavage site.
1 . A selective delivery molecule conjugate comprising:
(a) a selective delivery molecule of Formula I or Formula II, having the structure:
A-X-B-[ c B -D B ] Formula I
A-[ c M -M]-X-B-[ c B -D B ] Formula II
wherein,
X of Formula I or Formula II is a cleavable linker;
A of Formula I or Formula II is a peptide with a sequence comprising 5 to 9 acidic amino acids;
B of Formula I or Formula II is a peptide with a sequence comprising 7 to 9 basic amino acids;
c B of Formula I or Formula II is 0-1 amino acid;
c M of Formula I or Formula II is 0-1 amino acid;
M of Formula II is a macromolecule;
D B of Formula I or Formula II is a therapeutic agent or an imaging agent;
wherein [c M -M] of Formula II is bound to at any position on A or X; [c B -D B ] of Formula I or Formula II is bound to any amino acid on B; and
(b) a carrier or targeting ligand, wherein the carrier or targeting ligand is covalently bound to the selective delivery molecule.
2 . The molecule of claim 1 , wherein the carrier or targeting ligand is covalently bound to any amino acid of A or any amino acid of B.
3 . The molecule of claim 1 , wherein the targeting ligand is an antibody or a ligand that binds to a cell surface receptor.
4 . The molecule of claim 1 , wherein the targeting ligand binds to a tumor antigen or tumor-specific receptor.
5 . The molecule of claim 1 , wherein the targeting antibody is gemtuzumab, inotuumab, trastuzumab, lorvotuzumab, imgn388, SAR3419, BilB062, brentixumab, glembatumumab, SGN-75, PSMA ADC, ASG-5ME or mdx-1203.
6 . The molecule of claim 1 , wherein the carrier is a polyethylene glycol (PEG) polymer.
7 . The molecule of claim 1 , wherein the therapeutic agent is a chemotherapeutic agent, a cytotoxin, a steroid, an immunotherapeutic agent, a targeted therapy, or an anti-inflammatory agent.
8 . The molecule of claim 1 , wherein the therapeutic agent is doxorubicin, calicheamicin, maytansinoid, auritstatin, taxol, or cortisone.
9 . The molecule of claim 1 , wherein c B and c M are each selected from any amino acid having a free thiol group, any amino acid with free amine, any amino acid having a N-terminal amine group, and any amino acid with a side chain capable of forming an oxime or hydrazone bond upon reaction with a hydroxylamine or hydrazine group.
10 . The molecule of claim 1 , wherein c B and c M are each selected from D-cysteine, D-glutamate, lysine, and para-4-acetyl L-phenylalanine.
11 . The molecule of claim 1 , wherein c M is any amino acid with a side chain capable of forming an oxime or hydrazone bond upon reaction with a hydroxylamine or hydrazine group.
12 . The molecule of claim 1 , wherein X is cleavable by an extracellular protease.
13 . The molecule of claim 1 , wherein X comprises an amino acid sequence selected from: PLGLAG, PLG-C(me)-AG, RPLALWRS, ESPAYYTA, DPRSFL, PPRSFL, RLQLKL, and RLQLK(Ac).
14 . The molecule of claim 1 , wherein M is selected from a protein, a natural polymer, a synthetic polymer, or a dendrimer.
15 . The molecule of claim 1 , wherein M is selected from dextran, a polyethylene glycol (PEG) polymer, albumin, or a combination thereof.
16 . The molecule of claim 1 , wherein M is selected from PEG 1 kDa, PEG 2 kDa, PEG 3 kDa, PEG 4 kDa, PEG 5 kDa, PEG 10 kDa, PEG 12 kDa, PEG 15 kDa, PEG 20 kDa, PEG 30 kDa, and PEG40 kDa.
17 . The molecule of claim 1 , wherein the selective delivery molecule is: SDM-101, SDM-102, SDM-103, SDM-104, SDM-105, SDM-106, SDM-107, SDM-108, SDM-109, SDM-110, SDM-111, SDM-112, SDM-113, SDM-114, SDM-115, SDM-116, SDM-117, SDM-118, SDM-119, SDM-120, SDM-121, SDM-122, SDM-123, SDM-124, SDM-125, SDM-126, SDM-127, SDM-128, SDM-129, SDM-130, SDM-131, SDM-132, SDM-133, SDM-134, SDM-135, SDM-136, SDM-137, SDM-138, SDM-139, SDM-140, SDM-141, SDM-142, SDM-143, SDM-144, SDM-145, SDM-146, SDM-147, SDM-148, SDM-149, SDM-150, SDM-151, SDM-152, and SDM-153.
18 . A selective delivery molecule conjugate comprising:
(a) a selective delivery molecule of Formula V, having the structure:
A-[ c M -M]-X-B-Y-[ c B -D B ] Formula V
wherein,
X is a cleavable linker;
Y is a cleavable linker;
A is a peptide with a sequence comprising 5 to 9 acidic amino acids;
B is a peptide with a sequence comprising 7 to 9 basic amino acids;
c B and c M each independently comprise 0-1 amino acid;
M is a macromolecule;
D B is a therapeutic agent or an imaging agent,
wherein [c M -M] is bound to at any position on A or X, and [c B -D B ] is bound to any amino acid on B.
19 . The molecule of claim 18 , further comprising a carrier or targeting ligand, wherein the carrier or targeting ligand covalently bound to the selective delivery molecule
20 . The molecule of claim 19 , wherein the carrier or targeting ligand is covalently bound to any amino acid of A or any amino acid of B.
21 . The molecule of claim 19 , wherein the targeting ligand is an antibody or a ligand that binds to a cell surface receptor.
22 . The molecule of claim 19 , wherein the targeting antibody binds to a tumor antigen or a tumor antigen or tumor-specific receptor.
23 . The molecule of claim 19 , wherein the targeting antibody is gemtuzumab, inotuumab, trastuzumab, lorvotuzumab, imgn388, SAR3419, BilB062, brentixumab, glembatumumab, SGN-75, PSMA ADC, ASG-5ME or mdx-1203.
24 . The molecule of claim 18 , wherein the therapeutic agent is a chemotherapeutic agent, a cytotoxin, a steroid, an immunotherapeutic agent, a targeted therapy, or an anti-inflammatory agent.
25 . The molecule of claim 18 , wherein the therapeutic agent is doxorubicin, calicheamicin, maytansinoid, auritstatin or cortisone.
26 . The molecule of claim 18 , wherein c B and c M are each independently selected from a D amino acid, a L amino acid, an α-amino acid, a β-amino acid, or a γ-amino acid.
27 . The molecule of claim 18 , wherein c B and c M are each independently selected from any amino acid having a free thiol group, any amino acid with amine group, any amino acid having a N-terminal amine group, and any amino acid with a side chain capable of forming an oxime or hydrazone bond upon reaction with a hydroxylamine or hydrazine group.
28 . The molecule of claim 18 , wherein c B and c M are each independently selected from D-cysteine, D-glutamate, lysine, and para-4-acetyl L-phenylalanine.
29 . The molecule of claim 18 , wherein c M is any amino acid with a side chain capable of forming an oxime or hydrazone bond upon reaction with a hydroxylamine or hydrazine group.
30 . The molecule of claim 18 , wherein X is cleavable by an extracellular protease.
31 . The molecule of claim 18 , wherein X comprises an amino acid sequence selected from: PLGLAG, PLG-C(me)-AG, RPLALWRS, ESPAYYTA, DPRSFL, PPRSFL, RLQLKL, and RLQLK(Ac).
32 . The molecule of claim 18 , wherein Y is cleavable by an intracellular protease.
33 . The molecule of claim 18 , wherein Y is cleavable by a lysosomal protease.
34 . The molecule of claim 18 , wherein Y is cleavable by a cathepsin or a caspase.
35 . The molecule of claim 18 , wherein Y is cleavable by Cathepsin B.
36 . The molecule of claim 18 , wherein Y comprises a self-immolative spacer.
37 . The molecule of claim 18 , wherein Y comprises a PABC spacer, a PABOH spacer, a BHMS spacer or any derivative thereof.
38 . The molecule of claim 18 , wherein M is selected from a protein, a natural polymer, a synthetic polymer, or a dendrimer.
39 . The molecule of claim 18 , wherein M is selected from dextran, a polyethylene glycol (PEG) polymer, albumin, or a combination thereof.
40 . The molecule of claim 18 , wherein M is selected from PEG 1 kDa, PEG 2 kDa, PEG 3 kDa, PEG 4 kDa, PEG 5 kDa, PEG 10 kDa, PEG 12 kDa, PEG 15 kDa, PEG 20 kDa, PEG 30 kDa, and PEG40 kDa.
41 . The molecule of claim 18 , wherein the selective delivery molecule of Formula V is: SDM-101, SDM-102, SDM-103, SDM-104, SDM-105, SDM-106, SDM-107, SDM-108, SDM-109, SDM-110, SDM-111, SDM-112, SDM-113, SDM-114, SDM-115, SDM-116, SDM-117, SDM-118, SDM-119, SDM-120, SDM-121, SDM-122, SDM-123, SDM-124, SDM-125, SDM-126, SDM-127, SDM-128, SDM-129, SDM-130, SDM-131, SDM-132, SDM-133, SDM-134, SDM-135, SDM-136, SDM-137, SDM-138, SDM-139, SDM-140, SDM-141, SDM-142, SDM-143, SDM-144, SDM-145, SDM-146, SDM-147, SDM-148, SDM-149, SDM-150, SDM-151, SDM-152, and SDM-153.
42 . A pharmaceutical composition comprising a selective delivery molecule conjugate of claim 1 or claim 18 and one or more pharmaceutically acceptable carriers, glidants, diluents, or excipients.
43 . A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective delivery molecule conjugate of claim 1 or claim 18 , thereby treating the cancer.
44 . The method of claim 43 , wherein the cancer is a breast cancer, colorectal cancer, ovarian cancer, lung cancer, esophageal cancer, pancreatic cancer, gastro-intestinal cancer, squamous cell carcinoma, prostate cancer, melanoma, or thyroid cancer.
45 . A method for treating inflammation or an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a selective delivery molecule of claim 1 or claim 18 , thereby treating the inflammation or inflammatory disease.
46 . The method of claim 45 , wherein the inflammation is associated with rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, sepsis, erythema nodosum leprosum, multiple sclerosis, psoriasis, systemic lupus erythematosis, type I diabetes, atherosclerosis, encephalomyelitis, Alzheimer's disease, stroke, traumatic brain injury, Parkinson's disease or septic shock.