Compounds comprising self-immolative group
Provided are methods of use of compounds comprising a self-immolative group, which compounds may include a protein (for example, an oligopeptide, a polypeptide, an antibody, or the like) having substrate-specificity for a target and an active agent (for example, a drug, a toxin, a ligand, a detection probe, or the like) having a specific function or activity.
1. A method of treating a disease selected from an autoimmune disorder, a cancer, a viral infection, a bacterial infection, a fungal infection, and a parasitic infection, comprising administering an antibody-drug conjugate comprising a self-immolative group represented by the following Chemical Formula 1:
G is a glucuronic acid moiety or
wherein R 3 is hydrogen or a carboxyl protecting group, and each R 4 is independently hydrogen or a hydroxyl protecting group;
A is an antibody;
B is an active agent;
W is —C(O)—, —C(O)NR′—, —C(O)O—, —SO 2 NR′—, —P(O)R″NR′—, —SONR′—, or —PO 2 NR′—, in each case wherein the C(O), S, or P is directly bound to the phenyl ring, and R′ and R″ are each independently hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 8 )alkoxy, (C 1 -C 8 )alkylthio, mono- or di-(C 1 -C 8 )alkylamino, (C 3 -C 20 )heteroaryl or (C 6 -C 20 )aryl;
Z is hydrogen, (C 1 -C 8 )alkyl, halogen, cyano, or nitro;
n is an integer of 1 to 3, and when n is an integer of 2 or more, each of the Z(s) are the same as or different from each other;
L is a linker connecting A and W,
comprising at least one isoprenyl derivative unit represented by the following Chemical Formula A, which is recognized by an isoprenoid transferase
and
R 1 and R 2 are each independently hydrogen, (C 1 -C 8 )alkyl, or (C 3 -C 8 )cycloalkyl.
2. The method of claim 1 , wherein G is
R 3 is hydrogen or a carboxyl protecting group, and R 4 (s) are each independently hydrogen or a hydroxyl protecting group.
3. The method of claim 1 , wherein W is —C(O)—, —C(O)NR′—, or —C(O)O—.
4. The method of claim 1 , wherein the linker L is an alkylene having 1 to 50 carbon atoms and satisfies at least one of the following (i) to (iv):
(i) the alkylene includes at least one unsaturated bond,
(ii) the alkylene includes at least one heteroarylene,
(iii) at least one carbon atom of the alkylene is replaced with one or more hetero atoms selected from nitrogen (N), oxygen (O), and sulfur (S), and
(iv) the alkylene is substituted with one or more alkyls having 1 to 20 carbon atoms.
5. The method of claim 1 , wherein the linker L further includes a linking moiety represented by Chemical Formula B, C, D, or E:
L 1 is a single bond or alkylene having 1 to 30 carbon atoms;
R 11 is hydrogen or alkyl having 1 to 10 carbon atoms; and
L 2 is alkylene having 1 to 30 carbon atoms.
6. The method of claim 5 , wherein the linker L further includes a connection unit represented by the following Chemical Formula F or G:
—(CH 2 ) r (V(CH 2 ) p ) q — [Chemical Formula F]
—(CH 2 CH 2 X) w — [Chemical Formula G]
V is a single bond, —O—, —S—, —NR 21 —, —C(O)NR 22 —, —NR 23 C(O)—, —NR 24 SO 2 —, or —SO 2 NR 25 —;
X is —O—, (C 1 -C 8 )alkylene, or —NR 21 —;
R 21 to R 25 are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 20 )aryl, or (C 1 -C 6 )alkyl(C 3 -C 20 )heteroaryl;
r is an integer of 1 to 10;
p is an integer of 0 to 10;
q is an integer of 1 to 10; and
w is an integer of 1 to 10.
7. The method of claim 1 , wherein the antibody comprises an amino acid motif recognizable by an isoprenoid transferase.
8. The method of claim 7 , wherein the antibody further comprises a spacer unit comprising an amino acid, an oligopeptide, or a polypeptide between the antibody and the amino acid motif.
9. The method of claim 7 , wherein the antibody is covalently bonded to the linker L through the amino acid motif.
10. The method of claim 9 , wherein the antibody comprises a C-terminus that is a C-terminus of a light chain or a heavy chain of the antibody.
11. The method of claim 7 , wherein the isoprenoid transferase is farnesyl protein transferase (FTase) or geranylgeranyl transferase (GGTase).
12. The method of claim 1 , wherein the antibody is selected from intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments, single chain Fv (scFv) mutants, multispecific antibodies, bispecific antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins including an antigen determination portion of an antibody, and other modified immunoglobulin molecules including an antigen recognition site.
13. The method of claim 12 , wherein the antibody is selected from muromonab-CD3, abciximab, rituximab, daclizumab, palivizumab, infliximab, trastuzumab, etanercept, basiliximab, gemtuzumab ozogamicin, alemtuzumab, ibritumomab tiuxetan, adalimumab, alefacept, omalizumab, efalizumab, tositumomab-I 131 , cetuximab, bevacizumab, natalizumab, ranibizumab, panitumumab, eculizumab, rilonacept, certolizumab pegol, romiplostim, belimumab, tocilizumab, atlizumab, mepolizumab, pertuzumab, tremelimumab, ticilimumab, inotuzumab ozogamicin, aflibercept, catumaxomab, pregovomab, motavizumab, efumgumab, raxibacumab, and veltuzumab.
14. The method of claim 12 , wherein the antibody is a monoclonal antibody.
15. The method of claim 7 , wherein the amino acid motif is CYYX, XXCC, XCXC, or CXX, C representing cysteine, Y representing an aliphatic amino acid, and X representing an amino acid that determines a substrate specificity of the isoprenoid transferase.
16. The method of claim 1 , wherein the active agent is a drug, a toxin, an affinity ligand, a detection probe, or a combination thereof.
17. The method of claim 1 , wherein the active agent is an immunomodulatory compound, an anticancer agent, an antiviral agent, an antibacterial agent, an antifungal agent, an antiparasitic agent, or a combination thereof.
18. The method of claim 7 , wherein the amino acid motif is (G) z CVIM (SEQ ID NO: 1) or (G) z CVLL (SEQ ID NO: 2), with G representing a glycine unit, and z being an integer of 0 to 20.
19. The method of claim 18 , wherein the antibody-drug conjugate has a structure selected from:
wherein:
Z is hydrogen, (C 1 -C 8 )alkyl, halogen, cyano, or nitro;
X is —O—, (C 1 -C 8 )alkylene, or —NR 21 —;
R 21 is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 20 )aryl, or (C 1 -C 6 )alkyl(C 3 -C 20 )heteroaryl;
n is an integer of 1 to 3, and when n is an integer of 2 or more, each of the Z(s) are the same as or different from each other;
r is an integer of 1 to 10;
q is an integer of 1 to 10;
w is an integer of 1 to 10;
x is an integer of 0 to 10;
g is an integer of 1 to 10;
B is a drug having a structure selected from the following structures
and
y is an integer of 1 to 10.
20. The method of claim 1 , wherein the disease is an autoimmune disorder.
21. The method of claim 1 , wherein the disease is a cancer.
22. The method of claim 1 , wherein the disease is a viral infection.
23. The method of claim 1 , wherein the disease is a bacterial infection.
24. The method of claim 1 , wherein the disease is a fungal infection.
25. The method of claim 1 , wherein the disease is a parasitic infection.