US2019134196A1PendingUtilityA1
Etar antibody, and pharmaceutical compositions and use thereof
Est. expiryMay 31, 2036(~9.9 yrs left)· nominal 20-yr term from priority
C07K 2317/94A61P 9/12A61K 47/26C07K 16/2869A61K 47/183A61K 47/12A61K 47/10A61K 39/39591C07K 2317/24A61K 2039/505A61P 35/00A61K 47/22A61P 11/00A61K 39/395C07K 16/28A61K 47/20
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Abstract
Provided herein are a stable solution formulation of an ET A R antibody, and use thereof in treating, preventing, or alleviating one or more symptoms of pulmonary arterial hypertension or one or more symptoms of cancer of a reproductive organ.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A stable pharmaceutical solution formulation of an ET A R antibody, comprising an ET A R antibody and a buffer, wherein the formulation has a pH approximately ranging from 5 to 7.
2 . The formulation of claim 1 , wherein the ET A R antibody comprises 1, 2, 3, 4, 5, or 6 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below:
a. light chain CDR1 amino acid sequences: SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, and SEQ ID NO: 30; b. light chain CDR2 amino acid sequences: SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, and SEQ ID NO: 48; c. light chain CDR3 amino acid sequences: SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68; d. heavy chain CDR1 amino acid sequences: SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, and SEQ ID NO: 90; e. heavy chain CDR2 amino acid sequences: SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, and SEQ ID NO: 114; and f. heavy chain CDR3 amino acid sequences: SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, and SEQ ID NO: 136.
3 . The formulation of claim 1 or 2 , wherein the ET A R antibody comprises 1 or 2 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below:
a. light chain CDR1 amino acid sequences: SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, and SEQ ID NO: 30; and
b. heavy chain CDR1 amino acid sequences: SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, and SEQ ID NO: 90.
4 . The formulation of any one of claims 1 to 3 , wherein the ET A R antibody comprises 1 or 2 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below:
a. light chain CDR2 amino acid sequences: SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, and SEQ ID NO: 48; and
b. heavy chain CDR2 amino acid sequences: SEQ ID NO: 92, SEQ ID NO: 94, SEQ ID NO: 96, SEQ ID NO: 98, SEQ ID NO: 100, SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, and SEQ ID NO: 114.
5 . The formulation of any one of claims 1 to 4 , wherein the ET A R antibody comprises 1 or 2 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below:
a. light chain CDR3 amino acid sequences: SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68; and
b. heavy chain CDR3 amino acid sequences: SEQ ID NO: 116, SEQ ID NO: 118, SEQ ID NO: 120, SEQ ID NO: 122, SEQ ID NO: 124, SEQ ID NO: 126, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, and SEQ ID NO: 136.
6 . The formulation of any one of claims 1 to 5 , wherein the ET A R antibody comprises 1 or 2 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: SEQ ID NO: 8, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68.
7 . The formulation of any one of claims 1 to 6 , wherein the ET A R antibody comprises 1 or 2 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below: SEQ ID NO: 70, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 110, SEQ ID NO: 112, SEQ ID NO: 114, SEQ ID NO: 116, SEQ ID NO: 128, SEQ ID NO: 130, SEQ ID NO: 132, SEQ ID NO: 134, and SEQ ID NO: 136.
8 . The formulation of any one of claims 1 to 7 , wherein the ET A R antibody comprises a combination of amino acid sequences of light chain and heavy chain CDR3 independently selected from the list below: SEQ ID NO: 50 and SEQ ID NO: 116, SEQ ID NO: 62 and SEQ ID NO: 128, SEQ ID NO: 62 and SEQ ID NO: 130, SEQ ID NO: 64 and SEQ ID NO: 132, SEQ ID NO: 66 and SEQ ID NO: 134, and SEQ ID NO: 68 and SEQ ID NO: 136.
9 . The formulation of any one of claims 1 to 8 , wherein the ET A R antibody comprises 1 or 2 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below:
a. amino acid sequences of light chain variable domains: SEQ ID NO: 138, SEQ ID NO: 140, SEQ ID NO: 142, SEQ ID NO: 144, SEQ ID NO: 146, SEQ ID NO: 148, SEQ ID NO: 150, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 158, SEQ ID NO: 160, SEQ ID NO: 162, and SEQ ID NO: 164; and
b. amino acid sequences of heavy chain variable domains: SEQ ID NO: 166, SEQ ID NO: 168, SEQ ID NO: 170, SEQ ID NO: 172, SEQ ID NO: 174, SEQ ID NO: 176, SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 184, SEQ ID NO: 186, SEQ ID NO: 188, SEQ ID NO: 190, and SEQ ID NO: 192.
10 . The formulation of any one of claims 1 to 9 , wherein a polynucleotide coding sequence of the ET A R antibody comprises 1 or 2 polynucleotide sequences, wherein each polynucleotide sequence is independently selected from the polynucleotide sequences listed below:
a. The polynucleotide coding sequences of the light chain variable domains: SEQ ID NO: 137, SEQ ID NO: 139, SEQ ID NO: 141, SEQ ID NO: 143, SEQ ID NO: 145, SEQ ID NO: 147, SEQ ID NO: 149, SEQ ID NO: 151, SEQ ID NO: 153, SEQ ID NO: 155, SEQ ID NO: 157, SEQ ID NO: 159, SEQ ID NO: 161, and SEQ ID NO: 163; and
b. The polynucleotide coding sequences of the heavy chain variable domains: SEQ ID NO: 165, SEQ ID NO: 167, SEQ ID NO: 169, SEQ ID NO: 171, SEQ ID NO: 173, SEQ ID NO: 175, SEQ ID NO: 177, SEQ ID NO: 179, SEQ ID NO: 181, SEQ ID NO: 183, SEQ ID NO: 185, SEQ ID NO: 187, SEQ ID NO: 189, and SEQ ID NO: 191.
11 . The formulation of any one of claims 1 to 10 , wherein the ET A R antibody comprises a combination of amino acid sequences independently selected from the list below: SEQ ID NO: 138 and SEQ ID NO: 166, SEQ ID NO: 140 and SEQ ID NO: 168, SEQ ID NO: 142 and SEQ ID NO: 170, SEQ ID NO: 144 and SEQ ID NO: 172, SEQ ID NO: 146 and SEQ ID NO: 174, SEQ ID NO: 148 and SEQ ID NO: 176, SEQ ID NO: 150 and SEQ ID NO: 178, SEQ ID NO: 152 and SEQ ID NO: 180, SEQ ID NO: 154 and SEQ ID NO: 182, SEQ ID NO: 156 and SEQ ID NO: 184, SEQ ID NO: 158 and SEQ ID NO: 186, SEQ ID NO: 160 and SEQ ID NO: 188, SEQ ID NO: 162 and SEQ ID NO: 190, and SEQ ID NO: 164 and SEQ ID NO: 192.
12 . The formulation of any one of claims 1 to 11 , wherein the ET A R antibody comprises an amino acid sequence independently selected from the list below: SEQ ID NO: 138, SEQ ID NO: 150, SEQ ID NO: 152, SEQ ID NO: 154, SEQ ID NO: 156, SEQ ID NO: 158, SEQ ID NO: 160, SEQ ID NO: 162, and SEQ ID NO: 164.
13 . The formulation of any one of claims 1 to 12 , wherein the ET A R antibody comprises an amino acid sequence independently selected from the list below: SEQ ID NO: 166, SEQ ID NO: 178, SEQ ID NO: 180, SEQ ID NO: 182, SEQ ID NO: 184, SEQ ID NO: 186, SEQ ID NO: 188, SEQ ID NO: 190, and SEQ ID NO: 192.
14 . The formulation of any one of claims 1 to 13 , wherein the ET A R antibody comprises a combination of amino acid sequences of light chain and heavy chain variable domains independently selected from the list below: SEQ ID NO: 138 and SEQ ID NO: 166, SEQ ID NO: 150 and SEQ ID NO: 178, SEQ ID NO: 152 and SEQ ID NO: 180, SEQ ID NO: 154 and SEQ ID NO: 182, SEQ ID NO: 156 and SEQ ID NO: 184, SEQ ID NO: 158 and SEQ ID NO: 186, SEQ ID NO: 160 and SEQ ID NO: 188, SEQ ID NO: 162 and SEQ ID NO: 190, and SEQ ID NO: 164 and SEQ ID NO: 192.
15 . The formulation of any one of claims 1 to 14 , wherein the ET A R antibody comprises amino acid sequence SEQ ID NO: 138 or SEQ ID NO: 166.
16 . The formulation of any one of claims 1 to 15 , wherein the ET A R antibody comprises the combination of amino acid sequences SEQ ID NO: 138 and SEQ ID NO: 166.
17 . The formulation of any one of claims 2 to 16 , wherein the ET A R antibody comprises 1 or 2 amino acid sequences, wherein each amino acid sequence is independently selected from the amino acid sequences listed below:
a. amino acid sequences of light chain constant domains: SEQ ID NO: 194 and SEQ ID NO: 196; and
b. amino acid sequence of heavy chain constant domain: SEQ ID NO: 198.
18 . The formulation of any one of claims 1 to 17 , wherein the ET A R antibody comprises a murine ET A R antibody or a humanized ET A R antibody.
19 . The formulation of any one of claims 1 to 18 , wherein the ET A R antibody comprises a monoclonal ET A R antibody.
20 . The formulation of any one of claims 1 to 19 , wherein the ET A R antibody comprises a monoclonal antibody, wherein the monoclonal antibody comprises SEQ ID NO: 138 and SEQ ID NO: 166, SEQ ID NO: 150 and SEQ ID NO: 178, SEQ ID NO: 152 and SEQ ID NO: 180, SEQ ID NO: 154 and SEQ ID NO: 182, SEQ ID NO: 156 and SEQ ID NO: 184, SEQ ID NO: 158 and SEQ ID NO: 186, SEQ ID NO: 160 and SEQ ID NO: 188, SEQ ID NO: 162 and SEQ ID NO: 190, or SEQ ID NO: 164 and SEQ ID NO: 192.
21 . The formulation of any one of claims 1 to 20 , wherein the ET A R antibody has an IC 50 of approximately ranging from 1 nM to 200 nM or from 10 nM to 100 nM in reducing the signal transduction of endothelin.
22 . The formulation of any one of claims 1 to 21 , wherein the concentration of the ET A R antibody is approximately ranging from 10 to 200 mg/mL or from 10 to 100 mg/mL.
23 . The formulation of claim 22 , wherein the concentration of the ET A R antibody is approximately 25 mg/mL, 50 mg/mL, 75 mg/mL, or 100 mg/mL.
24 . The formulation of any one of claims 1 to 23 , wherein the concentration of the buffer is approximately ranging from 1 mM to 200 mM, from 2 mM to 50 mM, or from 5 mM to 25 mM.
25 . The formulation of any one of claims 1 to 24 , wherein the concentration of the buffer is approximately 10 mM, 15 mM, 20 mM, 25 mM, or 30 mM.
26 . The formulation of any one of claims 1 to 25 , wherein the buffer comprises a salt of citric acid or histidine.
27 . The formulation of any one of claims 1 to 26 , further comprising a surfactant.
28 . The formulation of claim 27 , wherein the surfactant comprises a polysorbate.
29 . The formulation of claim 27 or 28 , wherein the surfactant comprises polysorbate 20 or polysorbate 80.
30 . The formulation of claim 27 or 29 , wherein the concentration of the surfactant is approximately ranging from 0.001 to 1 weight/volume percent, from 0.01 to 0.5 weight/volume percent, or from 0.01 to 0.1 weight/volume percent.
31 . The formulation of claim 30 , wherein the concentration of the surfactant is approximately 0.02, 0.03, 0.04, 0.05, or 0.06 weight/volume percent.
32 . The formulation of any one of claims 1 to 31 , further comprising an amino acid protectant.
33 . The formulation of claim 32 , wherein the amino acid protectant comprises arginine or a salt thereof.
34 . The formulation of claim 32 or 33 , wherein the amino acid protectant comprises arginine hydrochloride.
35 . The formulation of any one of claims 32 to 34 , wherein the concentration of the amino acid protectant is approximately ranging from 1 mM to 500 mM or from 10 mM to 200 mM.
36 . The formulation of claim 35 , wherein the concentration of the amino acid protectant is approximately 120 mM, 130 mM, 140 mM, 150 mM, or 160 mM.
37 . The formulation of any one of claims 32 to 36 , wherein the concentration of the ET A R antibody is approximately ranging 10 to 200 mg/mL; the concentration of the surfactant is approximately ranging from 0.01 to 0.1 weight/volume percent; the concentration of the amino acid protectant is approximately ranging from 10 to 200 mM; and the concentration of the buffer is approximately ranging from 1 to 50 mM; wherein the pH of the formulation is approximately ranging from 5 to 7.
38 . The formulation of claim 37 , wherein the concentration of the ET A R antibody is approximately 25, 50, 75, or 100 mg/mL; the concentration of the surfactant is approximately 0.04 weight/volume percent; the concentration of the amino acid protectant is approximately 140 mM; and the concentration of the buffer is approximately 20 mM; wherein the pH of the formulation is approximately ranging from 5 to 6.
39 . The stable solution formulation of any one of claims 1 to 38 , further comprising a polyol protectant.
40 . The formulation of claim 39 , wherein the polyol protectant comprises sorbitol, mannitol, sucrose, or trehalose.
41 . The formulation of claim 39 or 40 , wherein the polyol protectant comprises sorbitol, mannitol, or sucrose.
42 . The formulation of claim 39 or 41 , wherein the concentration of the polyol protectant is approximately ranging from 0.1 to 50 weight/volume percent, from 1 to 20 weight/volume percent, or from 1 to 10 weight/volume percent.
43 . The formulation of claim 42 , wherein the concentration of the polyol protectant is approximately ranging from 4 to 10 weight/volume percent.
44 . The formulation of any one of claims 39 to 43 , wherein the concentration of the ET A R antibody is approximately ranging from 10 to 200 mg/mL; the concentration of the surfactant is approximately ranging from 0.01 to 0.1 weight/volume percent; the concentration of the polyol protectant is approximately ranging from 1 to 20 weight/volume percent; and the concentration of the buffer is approximately ranging from 1 to 50 mM; wherein the pH of the formulation is approximately ranging from 5 to 7.
45 . The formulation of claim 44 , wherein the concentration of the ET A R antibody is approximately 25, 50, 75, or 100 mg/mL; the concentration of the surfactant is approximately 0.04 weight/volume percent; the concentration of the polyol protectant is approximately ranging from 4 to 10 weight/volume percent; and the concentration of the buffer is approximately 20 mM; wherein the pH of the formulation is approximately ranging from 5 to 6.
46 . The formulation of any one of claims 1 to 45 , further comprising a metal chelator.
47 . The formulation of claim 46 , wherein the metal chelator comprises ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid, or ethylene glycol diethyl ether diaminetetraacetic acid.
48 . The formulation of claim 47 , wherein the metal chelator comprises ethylenediaminetetraacetic acid.
49 . The formulation of any one of claims 46 to 48 , wherein the concentration of the metal chelator is approximately ranging from 0.001 mM to 1 mM, from 0.005 mM to 0.5 mM, or from 0.01 mM to 0.2 mM.
50 . The formulation of claim 49 , wherein the concentration of the metal chelator is approximately 0.03 mM, 0.04 mM, 0.05 mM, 0.06 mM, or 0.07 mM.
51 . The formulation of any one of claims 46 to 50 , wherein the concentration of the ET A R antibody is approximately ranging from 10 to 200 mg/mL; the concentration of the metal chelator is approximately ranging from 0.01 mM to 0.2 mM; the concentration of the surfactant is approximately ranging from 0.01 to 0.1 weight/volume percent; the concentration of the amino acid protectant is approximately ranging from 10 to 200 mM; and the concentration of the buffer is approximately ranging from 1 to 50 mM; wherein the pH of the formulation is approximately ranging from 5 to 7.
52 . The formulation of claim 51 , wherein the concentration of the ET A R antibody is approximately 25, 50, 75, or 100 mg/mL; the concentration of the metal chelator is approximately 0.05 mM; the concentration of the surfactant is approximately ranging from 0.04 weight/volume percent; the concentration of the amino acid protectant is approximately 140 mM; and the concentration of the buffer is approximately 20 mM; wherein the pH of the formulation is approximately ranging from 5 to 6.
53 . The formulation of any one of the claims 46 to 50 , wherein the concentration of the ET A R antibody is approximately ranging from 10 to 200 mg/mL; the concentration of the metal chelator is approximately ranging from 0.01 mM to 0.2 mM; the concentration of the surfactant is approximately ranging from 0.01 to 0.1 weight/volume percent; the concentration of the polyol protectant is approximately ranging from 1 to 20 weight/volume percent; and the concentration of the buffer is approximately ranging from 1 to 50 mM; wherein the pH of the formulation is approximately ranging from 5 to 7.
54 . The formulation of the claim 53 , wherein the concentration of the ET A R antibody is approximately 25, 50, 75, or 100 mg/mL; the concentration of the metal chelator is approximately 0.05 mM; the concentration of the surfactant is approximately 0.04 weight/volume percent; the concentration of the polyol protectant is approximately ranging from 4 to 10 weight/volume percent; and the concentration of the buffer is approximately 20 mM; wherein the pH of the formulation is approximately ranging from 5 to 6.
55 . The formulation of any one of the claims 1 to 54 , further comprising an antioxidant.
56 . The formulation of the claim 55 , wherein the antioxidant comprises methionine, vitamin C, thiosulfate, thiosulfate, or benzyl methionine.
57 . The formulation of the claim 55 or 56 , wherein the antioxidant comprises methionine.
58 . The formulation of the claims 55 to 57 , wherein the concentration of the antioxidant is approximately ranging from 0.5 mM to 20 mM or from 1 mM to 10 mM.
59 . The formulation of the claim 58 , wherein the concentration of the antioxidant is approximately 3 mM, 4 mM, 5 mM, 6 mM, or 7 mM.
60 . The formulation of any one of the claims 55 to 59 , wherein the concentration of the ET A R antibody is approximately ranging from 10 to 200 mg/mL; the concentration of the antioxidant is approximately ranging from 1 mM to 10 mM; the concentration of the surfactant is approximately ranging from 0.01 to 0.1 weight/volume percent; the concentration of the amino acid protectant is approximately ranging from 10 to 200 mM; and the concentration of the buffer is approximately ranging from 1 to 50 mM; wherein the pH of the formulation is approximately ranging from 5 to 7.
61 . The formulation of the claim 60 , wherein the concentration of the ET A R antibody is approximately 25, 50, 75, or 100 mg/mL; the concentration of the antioxidant is approximately 5 mM; the concentration of the surfactant is approximately 0.04 weight/volume percent; the concentration of the amino acid protectant is approximately 140 mM; and the concentration of the buffer is approximately 20 mM; wherein the pH of the formulation is approximately ranging from 5 to 6.
62 . The formulation of any one of the claims 55 to 59 , wherein the concentration of the ET A R antibody is approximately ranging from 10 to 200 mg/mL; the concentration of the antioxidant is approximately ranging from 1 mM to 10 mM; the concentration of the surfactant is approximately ranging from 0.01 to 0.1 weight/volume percent; the concentration of the polyol protectant is approximately ranging from 1 to 20 weight/volume percent; and the concentration of the buffer is approximately ranging from 1 to 50 mM; wherein the pH of the formulation is approximately ranging from 5 to 7.
63 . The formulation of the claim 62 , wherein the concentration of the ET A R antibody is approximately 25, 50, 75, or 100 mg/mL; the concentration of the antioxidant is approximately 5 mM; the concentration of the surfactant is approximately ranging from 0.04 weight/volume percent; the concentration of the polyol protectant is approximately ranging from 4 to 10 weight/volume percent; and the concentration of the buffer is approximately ranging from 20 mM; wherein the pH of the formulation is approximately ranging from 5 to 6.
64 . The formulation of any one of the claims 1 to 63 , wherein the formulation is an aqueous solution.
65 . The formulation of any one of the claims 1 to 64 , wherein the formulation contains no more than about 10% of an aggregated ET A R antibody after 12-month of storage at 2-8° C.
66 . The formulation of any one of the claims 1 to 65 , wherein the extent of antibody degradation does not exceed about 10% after 12-month of storage at 2-8° C.
67 . The formulation of any one of the claims 1 to 66 , wherein the biological activity of the ET A R antibody is no less than 50% of the original biological activity after 12-month of storage at 2-8° C.
68 . A method of treating, preventing, or alleviating one or more symptoms of pulmonary arterial hypertension in a subject, comprising administering to the subject a therapeutically effective amount of the formulation of any one of claims 1 to 67 .
69 . A method of treating, preventing, or alleviating one or more symptoms of a disease associated with elevated pulmonary arterial pressure in a subject, comprising administering to the subject a therapeutically effective amount of the formulation of any one of claims 1 to 67 .
70 . A method of treating, preventing, or alleviating one or more symptoms of cancer of a reproductive organ in a subject, comprising administering to the subject a therapeutically effective amount of the formulation of any one of claims 1 to 67 .
71 . The method of the claim 70 , wherein the cancer of a reproductive organ is cancer of a reproductive organ accompanied with elevated pulmonary arterial pressure.
72 . The formulation of any one of the claims 78 to 71 , wherein the subject is a human.
73 . The formulation of any one of the claims 78 to 72 , wherein the formulation is administered intravenously or subcutaneously.Cited by (0)
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