US2018264131A1PendingUtilityA1
Hydrophilic self-immolative linkers and conjugates thereof
Est. expiryDec 21, 2032(~6.4 yrs left)· nominal 20-yr term from priority
A61P 35/00A61P 1/04A61P 11/00A61P 15/00A61P 1/18A61K 47/65C07K 7/02A61K 47/6863C07D 241/36C07D 295/192A61K 31/407A61K 38/06A61K 47/60A61K 47/6817A61K 47/6889C07D 295/182C07D 417/14A61K 31/404A61K 47/6803A61K 47/6851A61K 47/68031C07K 17/06A61K 31/496
60
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Claims
Abstract
The present disclosure provides compounds with a hydrophilic self-immolative linker, which is cleavable under appropriate conditions and incorporates a hydrophilic group to provide better solubility of the compound. The compounds of the present disclosure comprise a drug moiety, a targeting moiety capable of targeting a selected cell population, and a linker which contains an acyl unit, an optional spacer unit for providing distance between the drug moiety and the targeting moiety, a peptide linker which can be cleavable under appropriate conditions, a hydrophilic self-immolative linker, and an optional second self-immolative spacer or cyclization self-elimination linker.
Claims
exact text as granted — not AI-modified1 - 50 . (canceled)
51 : A method of killing a cell, comprising administering to the cell an amount of a compound, or a salt or solvate or stereoisomer thereof, sufficient to kill the cell, wherein the compound is of the formula (IIa):
wherein:
p is 1 to 20;
D is a drug moiety;
T is a targeting moiety;
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker;
L 4 is a bond or a spacer; and
A is an acyl unit.
52 : The method of claim 51 , wherein the cell is a cancer cell.
53 : The method of claim 52 , wherein the cancer cell is lymphoma cell, blastoma cell, melanoma cell, sarcoma cell, gastrointestinal cancer cell, a gastric cancer cell, pancreatic cancer cell, colorectal cancer cell, lung cancer cell, esophageal cancer cell, gallbladder cancer cell, head and neck cancer cell, liver cancer cell, endometrial carcinoma cell, uterine carcinoma cell, salivary gland carcinoma cell, breast cancer cell, cervical cancer cell, bladder cancer cell, prostate cancer cell, kidney cancer cell or ovarian cancer cell.
54 : A method of treating cancer in an individual in need thereof comprising administering to the individual an effective amount of a compound, or a salt or solvate or stereoisomer thereof, wherein the compound is of the formula (IIa):
wherein:
p is 1 to 20;
D is a drug moiety;
T is a targeting moiety;
R 1 is hydrogen, unsubstituted or substituted C 1-3 alkyl, or unsubstituted or substituted heterocyclyl;
L 1 is a bond, a second self-immolative linker, or a cyclization self-elimination linker;
L 2 is a bond or a second self-immolative linker;
wherein if L 1 is a second self-immolative linker or a cyclization self-elimination linker, then L 2 is a bond;
wherein if L 2 is a second self-immolative linker, then L 1 is a bond;
L 3 is a peptide linker,
L 4 is a bond or a spacer; and
A is an acyl unit.
55 : The method of claim 54 , wherein the cancer is lymphoma, blastoma, melanoma, sarcoma, gastrointestinal cancer, gastric cancer, pancreatic cancer, colorectal cancer, lung cancer, esophageal cancer, gallbladder cancer, head and neck cancer, liver cancer, endometrial carcinoma, uterine carcinoma, salivary gland carcinoma, breast cancer, cervical cancer, bladder cancer, prostate cancer, kidney cancer or ovarian cancer.
56 - 72 . (canceled)
73 : The method of claim 54 , wherein L 1 is a bond.
74 : The method of claim 54 , wherein L 1 is a second self-immolative linker or a cyclization self-elimination linker.
75 : The method of claim 74 , wherein L 1 is selected from the group consisting of
76 : The method of claim 54 , wherein L 2 is a bond.
77 : The method of claim 73 , wherein L 2 is a second self-immolative linker.
78 : The method of claim 54 , wherein L 3 is a peptide linker of 1 to 10 amino acid residues.
79 : The method of claim 54 , wherein L 3 is a peptide linker comprising an amino acid residue selected from lysine, D-lysine, citrulline, arginine, proline, histidine, ornithine, glutamine, valine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.
80 : The method of claim 79 , wherein L 3 is a dipeptide unit selected from valine-citrulline, proline-lysine, methionine-D-lysine, asparagine-D-lysine, isoleucine-proline, phenylalanine-lysine, and valine-lysine.
81 : The method of claim 80 , wherein L 3 is valine-citrulline.
82 : The method of claim 54 , wherein L 4 is a bond.
83 : The method of claim 54 , wherein L 4 is a spacer.
84 : The method of claim 83 , wherein the spacer is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
85 : The method of claim 83 , wherein L 4 is L 4a -C(O), L 4a -C(O)—NH, L 4a -S(O) 2 , or L 4a -S(O) 2 —NH, wherein each L 4a is independently polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
86 : The method of claim 83 , wherein L 4 is L 4a -C(O), wherein L 4a is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
87 : The method of claim 83 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyalkylene glycol.
88 : The method of claim 83 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyethylene glycol.
89 : The method of claim 83 , wherein the spacer is of the formula —CH 2 —(CH 2 —O—CH 2 ) m —CH 2 —C(O)—, wherein m is an integer from 0 to 30.
90 : The method of claim 54 , wherein A is selected from the group consisting of
wherein each Q 2 is NH or O, and each q is independently an integer from 1 to 10.
91 : The method of claim 90 , wherein A is selected from the group consisting of
wherein each Q 2 is independently NH or O and each q is independently an integer from 1 to 10.
92 : The method of claim 54 , wherein T is an antibody.
93 : The method of claim 54 , wherein T is: (a) an antibody comprising a heavy chain variable region comprising three CDRs from SEQ ID NO: 1 and a light chain variable region comprising three CDRs from SEQ ID NO: 2; or (b) an antibody comprising a heavy chain variable region comprising three CDRs from SEQ ID NO: 3 and a light chain variable region comprising three CDRs from SEQ ID NO: 4.
94 : The method of claim 92 , wherein one or more amino acid residues of the heavy chain of the antibody is replaced with a cysteine residue.
95 : The method of claim 92 , wherein one or more amino acid residues of the light chain is replaced with a cysteine residue.
96 : The method of claim 92 , wherein one or more amino acid residues of the heavy chain and the light chain is replaced with a cysteine residue.
97 : The method of claim 94 , wherein the one or more amino acid residues of the heavy chain of the antibody comprises an amino acid residue at position 157, 169 or 442 using EU numbering.
98 : The method of claim 92 , wherein D is linked to T by way of a cysteine residue.
99 : The method of claim 54 , wherein D is an amino-containing drug moiety, wherein the drug is connected to L 1 or X through the amino group.
100 : The method of claim 99 , wherein D is duocarmycin, dolastatin, tubulysin, doxorubicin (DOX), paclitaxel, or mitomycin C (MMC), or an amino derivative thereof.
101 : The method of claim 99 , wherein D is an amino derivative of duocarmycin selected from the group consisting of
102 : The method of claim 99 , wherein D is:
103 : The method of claim 54 , wherein -A-L 4 -L 3 -L 2 - is
104 : The method of claim 54 , wherein the
moiety is:
105 : The method of claim 54 , wherein the compound is formulated as a pharmaceutical composition comprising the compound or a salt or solvate or stereoisomer thereof, and a pharmaceutically acceptable carrier.
106 : The method of claim 54 , wherein the compound is of the formula (IIIa):
wherein p is 1, 2, 3 or 4; and T is an antibody comprising a heavy chain variable region comprising amino acids 1-118 of SEQ ID NO: 1 and a light chain variable region comprising amino acids 1-113 of SEQ ID NO. 2.
107 : The method of claim 54 , wherein the compound is of the formula (IVa):
wherein p is 1, 2, 3 or 4; and wherein T is an antibody comprising a heavy chain variable region comprising amino acids 1-118 of SEQ ID NO: 1 and a light chain variable region comprising amino acids 1-113 of SEQ ID NO. 2.
108 : The method of claim 54 , wherein the compound is of the formula (Va):
wherein p is 1, 2, 3 or 4; and wherein T is an antibody comprising a heavy chain variable region comprising amino acids 1-118 of SEQ ID NO: 1 and a light chain variable region comprising amino acids 1-113 of SEQ ID NO. 2.
109 : The method of claim 54 , wherein the compound is of the formula (IIIa):
wherein p is 1, 2, 3 or 4; and T is an antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO:2 (h5F1Ca. 1).
110 : The method of claim 54 , wherein the compound is of the formula (IVa):
wherein p is 1, 2, 3 or 4; and T is an antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO:2 (h5F1Ca. 1).
111 : The method of claim 54 , wherein the compound is of the formula (Va):
wherein p is 1, 2, 3 or 4; and T is an antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 1 and a light chain amino acid sequence of SEQ ID NO:2 (h5F1Ca. 1).
112 : The method of claim 110 , wherein the cancer is pancreatic cancer, gastric cancer or colorectal cancer.Cited by (0)
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