US2022396621A1PendingUtilityA1
Targeting agent antibody conjugates and uses thereof
Est. expiryMar 14, 2033(~6.6 yrs left)· nominal 20-yr term from priority
C07K 16/468A61K 47/542C07K 2317/55C07D 249/04C07K 16/3069C07K 2317/92C07K 2317/31C07K 16/2806A61K 2039/505C07K 16/32C07K 16/2803Y02A50/30C07K 16/2863C07C 275/24A61K 39/3955C07K 16/2809C07K 16/2887A61K 39/39558C07K 16/2896C07K 2317/33C07K 2317/73C07K 2317/94C07K 2317/52C07C 275/16A61P 35/02A61P 35/00C07K 2317/56C07K 2317/35C07K 16/2851A61P 17/00
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Claims
Abstract
Methods, compositions and uses are provided for bispecific antibodies comprising one or more unnatural amino acids. The bispecific antibodies may bind to two or more different receptors, coreceptors, antigens, or cell markers on one or more cells. The bispecific antibodies may be used to treat a disease or condition (e.g., cancer, autoimmune disease, pathogenic infection, inflammatory disease). The bispecific antibodies may be used to modulate (e.g., stimulate or suppress) an immune response.
Claims
exact text as granted — not AI-modifiedThat which is claimed is:
1 . A targeting agent antibody conjugate comprising:
a. a targeting agent that binds to a target cell, wherein the targeting agent is not an antibody or antibody fragment; and b. an antibody or antibody fragment that does not bind to the target cell; and c. one or more linkers,
wherein the antibody or antibody fragment is linked to the targeting agent by the one or more linkers and wherein the antibody or antibody fragment binds an antigen on a cytotoxic effector cell.
2 . The targeting agent antibody conjugate of claim 1 , wherein the antibody or antibody fragment comprises one or more unnatural amino acids.
3 . The targeting agent antibody conjugate of claim 2 , wherein the targeting agent is site-specifically linked by the one or more linkers to the one or more unnatural amino acids of the antibody or antibody fragment.
4 . The targeting agent antibody conjugate of claim 1 , wherein the targeting agent antibody conjugate is of Formula I: X-L1-Y or Formula IA: Y-L1-X, wherein:
a. X comprises the antibody or antibody fragment; b. L1 comprises the one or more linkers; and c. Y comprises the targeting agent.
5 . The antibody of claim 1 or 4 , wherein at least a portion of the antibody is based on or derived from a human, humanized, human engineered or fully human antibody.
6 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the antibody is a chimeric antibody.
7 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent binds a cell surface protein or a cell surface marker on the target cell.
8 . The targeting agent antibody conjugate of claim 7 , wherein the cytotoxic effector cell is capable of mounting an immune response.
9 . The targeting agent antibody conjugate of claim 7 , wherein the antigen is a T-cell receptor (TCR).
10 . The targeting agent antibody conjugate of claim 7 , wherein the antigen comprises a T-cell co-receptor.
11 . The targeting agent antibody conjugate of claim 10 , wherein the co-receptor is a CD3 T-cell co-receptor.
12 . The targeting agent antibody conjugate of claim 7 , wherein the cytotoxic effector cell is a hematopoietic cell.
13 . The targeting agent antibody conjugate of claim 12 , wherein the hematopoietic cell is selected from a macrophage, a neutrophil, an eosinophil, a natural killer cell, a B-cell, or a T-cell.
14 . The targeting agent antibody conjugate of claim 7 , wherein the cytotoxic effector cell is a cytotoxic T cell.
15 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the antibody or antibody fragment comprises an anti-CD3 Fab fragment.
16 . The targeting agent antibody conjugate of claim 15 , wherein the anti-CD3 Fab fragment is UCHT1.
17 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the antibody fragment is encoded by a sequence selected from SEQ ID NOs: 1 and 2.
18 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent is selected from a a cell-targeting molecule, a hormonal ligand, a protein, a peptide, a peptoid, a DNA aptamer and a peptide nucleic acid.
19 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent does not comprise an antibody or an antibody fragment.
20 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent binds a cell surface protein selected from a cholecystokinin B receptor, a gonadotropin-releasing hormone receptor, a somatostatin receptor 2, an avb3 integrin, a gastrin-releasing peptide receptor, a neurokinin 1 receptor, a melanocortin 1 receptor, a neurotensin receptor, neuropeptide Y receptor and C-type lectin like molecule 1.
21 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent binds a prostate specific membrane antigen.
22 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent is selected from an octreotide, an octreotate, a somatostatin analog, a CD38 NAD+ glycohydrolase inhibitor, a pentagastrin, a gonadotropin releasing hormone, a CCKB antagonist, a cRGD and a bombesin.
23 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent comprises 2-[3-(1,3-dicarboxypropy)ureidol] pentanedioic acid (DUPA).
24 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent antibody conjugate is sufficiently small to penetrate a tumor.
25 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the targeting agent is encoded by a sequence selected from SEQ ID NOs: 3-40.
26 . The targeting agent antibody conjugate of claim 1 or 4 , further comprising a second targeting agent.
27 . The targeting agent antibody conjugate of claim 7 , wherein the target cell is a cancerous cell.
28 . The targeting agent antibody conjugate of claim 27 , wherein the cancerous cell is derived from a prostate cancer.
29 . The targeting agent antibody conjugate of claim 27 , wherein the cancerous cell is derived from a cancer selected from an epithelial cancer, a breast cancer, a kidney cancer, a lung cancer, a colon cancer, a colorectal cancer, a gastric cancer, a brain cancer, a glioblastoma, a pancreatic cancer, a myeloid leukemia, a cervical cancer, a medullary thyroid carcinoma, a stromal ovarian cancer, an astrocytoma, an endometrial cancer, a neuroendocrine cancer, a gastroenteropancreatic tumor, a non-Hodgkin's lymphoma, an exocrine pancreatic cancer, an Ewing's sarcoma and a skin cancer.
30 . The targeting agent antibody conjugate of claim 4 , wherein X and/or Y is coupled to L1 by an oxime.
31 . The targeting agent antibody conjugate of claim 4 , wherein L1 provides between about 10 and about 100 angstrom (Å) distance between X and Y.
32 . The targeting agent antibody conjugate of claim 2 or 3 , wherein the one or more unnatural amino acids of the antibody or antibody fragment comprises a p-acetylphenylalanine (pAcF).
33 . The targeting agent antibody conjugate of claim 2 or 3 , wherein the one or more unnatural amino acids of the antibody or antibody fragment comprises a selenocysteine.
34 . A pharmaceutical composition comprising the targeting agent antibody conjugate of claims 1 - 33 .
35 . A method for treating a disease or condition in a subject in need thereof, comprising administering the targeting agent antibody conjugate of 1-33 or a composition of claim 34 .
36 . The method of claim 35 , wherein the disease or condition is a cancer.
37 . The method of claim 36 , wherein the cancer is a prostate cancer.
38 . The method of claim 36 , wherein the cancer is selected from an epithelial cancer, a kidney cancer, lung cancer, a colon cancer, a colorectal cancer, a gastric cancer, a brain cancer, a glioblastoma, a pancreatic cancer, a myeloid leukemia, a cervical cancer, a medullary thyroid carcinoma, a breast cancer, an ovarian cancer, an astrocytoma, an endometrial cancer, a neuroendocrine cancer, a gastroenteropancreatic tumor, a non-Hodgkin's lymphoma, an exocrine pancreatic cancer, an Ewing's sarcoma and a skin cancer.
39 . The method of claim 35 , wherein administering comprises use of a microneedle device.
40 . A targeting agent antibody conjugate comprising:
a. an anti-CD3 Fab; b. one or more DUPA molecules; and c. one or more linkers,
wherein the antibody or antibody fragment is linked to the one or more targeting agents by the one or more linkers.
41 . The targeting agent antibody conjugate of claim 41 , wherein the anti-CD3 Fab comprises one or more unnatural amino acids.
42 . The targeting agent antibody conjugate of claim 42 , wherein a first unnatural amino acid and a second unnatural amino acid replace a natural amino acid of the anti-CD3 Fab, wherein the natural amino acid is selected from Lysine 138 (Lys 138) of a heavy chain of the anti-CD3 Fab, Alanine 123 (Ala 123) of a heavy chain of the anti-CD3 Fab, Threonine 109 (Thr 109) of a heavy chain of the anti-CD3 Fab and Serine 202 (Ser 202) of a heavy chain of the anti-CD3 Fab.
43 . The targeting agent antibody conjugate of claim 42 , wherein a first DUPA molecule and a second DUPA molecule are site-specifically linked to a first unnatural amino acid and a second unnatural amino acid of the anti-CD3 Fab.
44 . The targeting agent antibody conjugate of claim 40 , wherein the targeting agent antibody conjugate is of Formula I: X-L1-Y or Formula IA: Y-L1-X, wherein:
a. X comprises the anti-CD3 Fab; b. L1 comprises the one or more linkers; and c. Y comprises one or more DUPA molecules.
45 . The targeting agent antibody conjugate of claim 44 , comprising a compound selected from the compounds of Formula V, Formula VI, Formula VII and Formula VIII:
46 . The targeting agent antibody conjugate of claim 44 , comprising a compound of Formula IX:
47 . The targeting agent antibody conjugate of claim 1 or 4 , comprising a compound of Formula X:
48 . The targeting agent antibody conjugate of claim 1 or 4 , comprising a compound of Formula XI:
49 . The targeting agent antibody conjugate of claim 1 or 4 , wherein the one or more linkers comprise a P-TriA derived linker.
50 . A compound of Formula XII:
Y-L-A 1 -L 1 -A 2 -L 2 -A 3 -L 3 -X 2 (Formula XII)
wherein:
Y is a ligand of prostate specific membrane antigen (PSMA);
L is
A1 is selected from the group consisting of an aryl, a 5- to 6-membered heteroaryl, —C(O)—, —O—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —S(O) 1,2 N(R 1 )—, and —N(R 1 )S(O) 1,2 —;
L1 is
A 2 is selected from the group consisting of a bond, —C(O)—, —N(R 1 )—, —O—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —S(O) 1,2 N(R 1 )—, and —N(R 1 )S(O) 1,2 —;
L 2 is
A 3 is a bond,
L 3 is
X 2 is a linker bound to a functional group that reacts with an unnatural amino acid, or a linker bound to a modified unnatural amino acid, wherein the modified unnatural amino acid is part of X, wherein X is a modified therapeutic peptide, protein, or antibody;
each R 1 is independently selected from H, alkyl, or haloalkyl;
each R 2 , R 21 , R 22 , and R 23 is independently selected from H, halo, —OR 1 , —CN, —SR 1 , alkyl, cycloalkyl, haloalkyl, arylalkyl, or heteroarylalkyl;
each R 3 is independently selected from halo, —OW, —CN, —SR 1 , alkyl, cycloalkyl, haloalkyl, arylalkyl, or heteroarylalkyl, —NO 2 , and NR 1 R 1 ;
each G 1 and G 2 is independently selected from the group consisting of a bond, —C(O)—, —N(R 1 )—, —O—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —S(O) 12 N(R 1 )—, and —N(R 1 )S(O) 12 —;
each Z, Z 1 , Z 2 , and Z 3 is independently selected from the group consisting of a bond, —O—, and —N(R 1 )—;
k, k 1 , k 2 and k 3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
m 1 , m 2 and m 3 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
p is 0, 1, 2, 3 or 4,
or a stereoisomer thereof.
51 . The compound of claim 50 , wherein the compound is of Formula XIIa:
wherein:
Q is selected from the group consisting of:
and
E is selected from the group consisting of:
52 . The compound of claim 51 , wherein the compound is of Formula XIIb:
53 . The compound of claim 52 , wherein the compound is of Formula XIIc:
54 . The compound of claim 51 , wherein the compound is of Formula XIId:
55 . The compound of claim 54 , wherein the compound is of Formula XIIe:
56 . The compound of claim 55 , wherein the compound is of Formula XIIf:
57 . The compound of any one of claims 50 - 56 , wherein:
A1 is —C(O)N(H)—.
58 . The compound of any one of claims 50 - 56 , wherein:
A 1 is
59 . The compound of any one of claims 50 - 58 , wherein:
A 3 is
60 . The compound of claim 59 , wherein:
A 3 is
61 . The compound of claim 50 wherein:
each R 2 , R 21 , R 22 , R 23 , and R 24 is independently selected from H, F, —CH 3 , or —CF 3 .
62 . The compound of claim 50 , wherein:
each R 2 , R 21 , R 22 , R 23 , and R 24 is H.
63 . The compound of any one of claims 50 - 62 , wherein:
X 2 is
wherein:
A 4 is selected from the group consisting of a bond, —C(O)—, —N(R 1 )—, —O—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —S(O) 1,2 N(R 1 )—, and —N(R 1 )S(O) 1,2 —;
each R 24 is independently selected from H, halo, —OR′, —CN, —SR′, alkyl, cycloalkyl, haloalkyl, arylalkyl, or heteroarylalkyl;
k 4 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
Z 4 is selected from a bond, aryl, and a 5- to 6-membered heteroaryl; and
X 1 is —ONH 2 ,
—N 3 ,
—N(H)NH 2 , or —SH.
64 . The compound of claim 63 , wherein:
X 2 is
65 . The compound of claim 64 , wherein:
X 2 is
66 . The compound of claim 50 , wherein the compound is selected from:
or a stereoisomer thereof.
67 . The compound of any one of claims 50 - 62 , wherein:
X 2 is
wherein:
A 4 is selected from the group consisting of a bond, —C(O)—, —N(R 1 )—, —O—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —S(O) 1,2 N(R 1 )—, and —N(R 1 )S(O) 1,2 —;
each R 24 is independently selected from H, halo, —OR′, —CN, —SR′, alkyl, cycloalkyl, haloalkyl, arylalkyl, or heteroarylalkyl;
k 4 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
Z 4 is selected from a bond, aryl, and a 5- to 6-membered heteroaryl; and
X 3 is
or —S—;
X is a modified therapeutic peptide, protein, or antibody;
L 4 is a bond directly attached to a modified amino acid, or a linker bound to a modified amino acid, wherein the modified amino acid is part of X.
68 . The compound of any of claims 50 - 67 , wherein the amino acid is an unnatural amino acid.
69 . A composition comprising a targeting agent antibody conjugate of claims 1 - 33 or a compound of claims 50 - 68 .
70 . The composition of claim 69 , wherein the purity of the targeting agent antibody conjugate or the compound is at least 90%.
71 . A method for treating a prostate cancer in a subject in need thereof, comprising administering a targeting agent antibody construct of claims 1 - 33 or a compound of claims 50 - 70 .Join the waitlist — get patent alerts
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