US2024033372A1PendingUtilityA1
Multi-drug antibody drug conjugates
Est. expiryDec 14, 2036(~10.4 yrs left)· nominal 20-yr term from priority
Inventors:Matthew Levengood
A61K 47/68031A61K 47/6803A61K 47/68037A61K 39/00A61K 47/6889A61K 31/496C07K 16/2803A61K 47/61A61K 47/6883A61K 47/60A61K 47/6809A61K 47/6849A61K 31/4745A61K 31/704A61K 47/6817A61K 47/6851A61K 45/06A61P 35/00C07K 16/30A23K 50/10A61K 47/6843C07K 16/2878A61K 47/6805A61K 31/351A61K 38/00A61K 38/05
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Claims
Abstract
The present disclosure provides, inter alia, multi-drug Antibody Drug Conjugates (MD-ADCs) and Linking Assembly (LA) Units that are constructed in a site-specific matter via “orthogonal” deprotection and drug loading. Also provided are, Protected Linking Assembly Units, which allow for ‘orthogonal’ deprotection and construction of MD-ADCs and LA Units of the present disclosure.
Claims
exact text as granted — not AI-modified1 - 27 . (canceled)
28 . A Drug Linking Assembly Unit having the formula (Ia), (IIa), (IIIa), or (IVa):
wherein
T is a Tethering Group capable of attaching to a sulfur atom from a reduced interchain disulfide bond in an antibody;
Q 1 is a first Attachment Group;
Q 2 is a second Attachment Group;
X, X 1 , and X 2 are each independently i-s an Attachment Group Linker;
D 1 is a first Drug Unit;
D 2 is a second Drug Unit;
L 1 is an Optional Linking Group joining D 1 to Q 1 ;
L 2 is an Optional Linking Group joining D 2 to Q 2 ;
subscripts m 1 and m 2 are each independently 0 or 1;
Y is a Partitioning Agent that is attached to a site on Q 1 , X, X 1 , X 2 , Q 2 , L 1 or L 2 ; and
subscript n is 0 or 1.
2 - 31 . (canceled)
32 . The Drug Linking Assembly Unit of claim 28 , wherein each of L 1 and L 2 comprises a succinimido group.
33 . The Drug Linking Assembly Unit of claim 28 , wherein each of L 1 and L 2 comprises a succinimido group, and each of X, X 1 , X 2 , Q 1 , and Q 2 is independently an amino acid.
34 . The Drug Linking Assembly Unit of claim 33 , wherein subscript n is 0 and Y is absent.
35 . The Drug Linking Assembly Unit of claim 33 , wherein subscript n is 0, Y is absent, and each of L 1 and L 2 is independently selected from the group consisting of maleimido-caproyl (me), maleimido-caproyl-valine-citrulline (mc-vc), and maleimido-caproyl-valine-citrulline-paraaminobenzyloxycarbonyl (mc-vc-PABC), wherein the maleimido group is replaced by a succinimido group, optionally in a hydrolyzed form.
36 . The Drug Linking Assembly Unit of claim 28 , wherein T comprises a terminal maleimido group.
37 . The Drug Linking Assembly Unit of claim 36 , wherein T is a self-stabilizing linker.
38 . The Drug Linking Assembly Unit of claim 36 , wherein T comprises the Formula (VII) of:
wherein R PR is hydrogen or a protecting group, subscript m is 1 or 2, and R 23 is —NH—C 1-5 alkylene-C(═O)—, or a mono, di-, tri-, tetra-, or penta-peptide.
39 . The Drug Linking Assembly Unit of claim 36 , wherein T comprises the Formula of:
40 . The Drug Linking Assembly Unit of claim 36 , wherein T is a MDPr-vc linker.
41 .- 85 . (canceled)
86 . The Drug Linking Assembly Unit of claim 28 , wherein D 1 and D 2 are a first anticancer agent and a second anticancer agent, respectively.
87 . The Drug Linking Assembly Unit of claim 86 , wherein the first anticancer agent and the second anticancer agent have complementary activity profiles.
88 . The Drug Linking Assembly Unit of claim 86 , wherein the first anticancer agent and the second anticancer agent are MMAE and MMAF or camptothecin and doxorubicin.
89 . The Drug Linking Assembly Unit of claim 28 , wherein the Partitioning Agent is a polyethylene glycol unit or cyclodextrin unit.
90 . The Drug Linking Assembly Unit of claim 28 , wherein Q 1 is cysteine having D 1 attached via L 1 to the sulfur atom of the cysteine of Q 1 ; and Q 2 is cysteine having D 2 attached via L 2 to the sulfur atom of the cysteine of Q 2 .
91 . The Drug Linking Assembly Unit of claim 28 , wherein D 1 and D 2 are independently selected from the group consisting of MMAE, Auristatin T, MMAF and Dolastatin 10; or the group consisting of MMAE, camptothecin, Superdox, Dolastatin 10, Vinblastine and Ciprofloxacin.
92 . The Drug Linking Assembly Unit of claim 28 , wherein T comprises the formula of:
wherein the wavy light is an Attachment Group, and R 19 is C 1 -C 10 alkylene-, C 1 -C 10 heteroalkylene-, C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, (C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-,C 3 -C 8 heterocyclo-, C 1 -C 10 alkylene-(C 3 -C 8 , heterocyclo), (C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, C 1 -C 10 alkylene-C(═O)—, C 1 -C 10 heteroalkylene-C(═O)—,C 3 -C 8 carbocyclo-C(═O)—, —O—(C 1 -C 8 alkyl)-C(═O)—, -arylene-C(═O), C 1 -C 10 alkylene-arylene-C(═O)—, -arylene-C 1 -C 10 alkylene-C(═O)—, C 1 -C 8 alkylene-(C 3 -C 8 , carbocyclo)-C(═O)—, (C 3 -C 5 carbocyclo)-C 1 -C 10 alkylene-C(═O)—, C 3 -C 8 heterocyclo-C(═O)—, C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-C(═O)—, (C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-C(═O)—,C 1 -C 10 alkylene-NH—, C 1 -C 10 heteroalkylene-NH—, C 3 -C 8 carbocyclo-NH—, —O—(C 1 -C 8 alkyl)-NH—, -arylene-NH, C 1 -C 10 alkylene-arylene-NH,-arylene-C 1 -C 10 alkylene-NH—, C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-NH—, (C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-NH—, C 3 -C 8 heterocyclo-NH—, C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-NH—, (C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-NH—, C 1 -C 10 alkylene-S—, C 1 -C 10 heteroalkylene-S—, C 3 -C 8 carbocyclo-S—, —O—(C 1 -C 8 alkyl)-S—, -arylene-S—, C 1 -C 10 alkylene-arylene-S—, -arylene-C 1 -C 10 alkylene-S—, C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-S—, (C 3 -C 8 carbocyclo)-C 1 -C 8 alkylene-S—, C 3 -C 8 heterocyclo-S—, C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-S—, or (C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-S—.
93 . The Drug Linking Assembly Unit of claim 28 , wherein T comprises the formula of:
94 . The Drug Linking Assembly Unit of claim 38 , wherein R 23 is —NH—CH 2 —C(═O)—.
95 . A Drug Linking Assembly Unit, wherein the Drug Linking Assembly Unit is selected from the group consisting of:
wherein
Comp. Aa is:
Comp. Ab is:
Comp. Ac is:
Comp. Ad is:
Comp. Ae is:
Comp. Af is:
Comp. Ag is:
Comp. Ah is:
Comp. Ai is:
Comp. Aj is:
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