EXTRACELLULAR TARGETED DRUG CONJUGATES
Extracellular drug conjugates (EDCs) targeting an extracellular protein or portion thereof (e.g., CD38) and comprising a non-cleavable linker including one or two nitrogen heteroatoms are useful in the treatment of diseases such as cancer and immune disorders, including asthma.
1 . An extracellular-targeted drug conjugate (EDC) comprising a targeting moiety linked by a stable or non-cleavable linker to an agent, wherein the targeting moiety binds to an extracellular protein or fragment thereof, wherein the agent binds to or modifies the activity of a Na,K-ATPase, and wherein the non-cleavable linker includes one or two nitrogen heteroatoms.
2 . The EDC of claim 1 , wherein the one or two nitrogen heteroatoms includes at least one amine nitrogen atom.
3 . The EDC of claim 2 , wherein the at least one amine nitrogen atom includes a primary amine nitrogen atom.
4 . The EDC of claim 2 , wherein the at least one amine nitrogen atom includes a secondary amine nitrogen atom.
5 . The EDC of claim 2 , wherein the at least one amine nitrogen atom includes a tertiary amine nitrogen atom.
6 . The EDC of claim 2 , wherein the at least one amine nitrogen atom includes a quaternary amine nitrogen atom.
7 . The EDC of claim 1 , wherein the one or two nitrogen heteroatoms is located between a spacer portion of the non-cleavable linker and the agent.
8 . The EDC of claim 7 , wherein the spacer portion comprises a polyethylene glycol.
9 . The EDC of claim 1 , wherein the agent is a cardiac glycoside.
10 . The EDC of claim 1 , wherein the agent is a cardenolide or cardiotonic steroid.
11 . The EDC of claim 10 , wherein the cardiotonic steroid is bufalin, digitoxigenin, scillarenin, or a derivative of any of the foregoing.
12 . An extracellular-targeted drug conjugate (EDC) of Formula (I):
[TARGETING MOIETY]-(-[LINKER]-[AGENT]) n Formula (I)
wherein:
[Targeting Moiety] is an antibody that binds to CD38;
[Agent] is a cardiotonic steroid or a cardenolide; and
[Linker] has a formula of Formula (II):
wherein: X 1 is optionally present and when present is
and d is 0 to 6;
X 2 , X 3 and X 4 are each optionally present and when present are individually selected from alkyl, ketone, —C(O)NH—, —C(O)NR 8 —, —O—, —S—, —NH—, —NR 9 —, wherein R 8 and R 9 are individually selected from alkyl (e.g., methyl), heteroalkyl, aryl, and heteroaryl;
X 5 and X 6 are each individually selected from CR 10 and N, wherein R 10 is H, branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl;
X 7 is optionally present and when present is selected from —C(O)—, —C(O)—, —NHC(O)—, —NR 11 C(O)—, wherein R 11 is H, branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl;
R 1 is optionally present and when present is selected from branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl;
each of R 2 , R 3 and R 6 is optionally be present and when present each is individually selected from branched alkyl, unbranched alkyl, saturated alkyl, and unsaturated alkyl;
each of R 4 and R 5 is optionally present and when present is individually selected from branched alkyl, unbranched alkyl, saturated alkyl, or unsaturated alkyl, with the proviso that at least one of R 4 and R 5 must be present;
a is 0 to 99;
b is 0 to 99;
c is 0 to 99; and
n is about 1 to about 10.
13 . The EDC of claim 12 , wherein
X 1 is
and d is 2;
X 2 is —O—;
X 3 is null;
X 4 is —NH—;
X 5 and X 6 are each N;
R 1 , R 2 , R 4 and R 5 are each —CH 2 CH 2 —;
X 7 is —NHC(O)—;
R 3 and R 6 are each —CH 2 CH 2 CH 2 —;
a is 24;
b is 1;
c is 1; and
n is about 4 to about 8.
14 . The EDC of claim 12 , wherein the targeting moiety binds to the same or substantially the same epitope of CD38 as SUN4B7.
15 . The EDC of claim 14 , wherein the targeting moiety comprises SUN4B7.
16 . The EDC of claim 12 , wherein the agent is bufalin.
17 . The EDC of claim 1 , wherein the targeting moiety is CEN-Ab-107.
18 . The EDC of claim 17 , wherein the EDC does not bind to cardiac cells.
19 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 4.
20 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 6.
21 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 8.
22 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 9.
23 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 10.
24 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 11.
25 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 5.
26 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 7.
27 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 12.
28 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 13.
29 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 14.
30 . The EDC of claim 18 , wherein the CEN-Ab-107 comprises SEQ ID NO: 15.
31 . A method for treating a disease comprising administering to a subject in need of treatment for said disease a therapeutically effective amount of the EDC of any one of claim 1 , wherein the disease is optionally an immune disease such as asthma.