Hydrophilic self-immolative linkers and conjugates thereof
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.
1. A compound of the formula (IIa):
or a salt or solvate or stereoisomer thereof;
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-irnmolative 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.
2. The compound of claim 1 , wherein p is 1 to 4.
3. The compound of claim 1 , wherein L 1 is a bond.
4. The compound of claim 1 , wherein L 1 is a second self-immolative linker or a cyclization self-elimination linker.
5. The compound of claim 1 , wherein L 2 is a bond.
6. The compound of claim 3 , wherein L 2 is a second self-immolative linker.
7. The compound of claim 1 , wherein L 3 is a peptide linker of 1 to 10 amino acid residues.
8. The compound of claim 7 , wherein L 3 is a peptide linker of 2 to 4 amino acid residues.
9. The compound of claim 1 , wherein L 3 is a peptide linker comprising an amino acid residue selected from lysine, D-lysine, citrulline, arginine, proline, histidine, ornithine and glutamine.
10. The compound of claim 1 , wherein L 3 is a peptide linker comprising an amino acid residue selected from valine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine.
11. The compound of claim 7 , 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.
12. The compound of claim 11 , wherein L 3 is valine-citrulline.
13. The compound of claim 1 , wherein L 4 is a bond.
14. The compound of claim 1 , wherein L 4 is a spacer.
15. The compound of claim 14 , wherein the spacer is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
16. The compound of claim 14 , 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.
17. The compound of claim 14 , wherein L 4 is L 4a -C(O), wherein L 4a is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
18. The compound of claim 14 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyalkylene glycol.
19. The compound of claim 14 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyethylene glycol.
20. The compound of claim 14 , 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.
21. The compound of claim 1 , 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.
22. The compound of claim 21 , 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.
23. The compound of claim 22 , wherein q is 2, 3, 4, or 5.
24. The compound of claim 1 , wherein T is an antibody.
25. The compound of claim 24 , wherein 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) or an antibody comprising a heavy chain amino acid sequence of SEQ ID NO:3 and a light chain amino acid sequence of SEQ ID NO:4 (c5D7).
26. The compound of claim 24 , wherein one or more amino acid residues of the heavy chain and/or the light chain is replaced with a cysteine residue.
27. The compound of claim 24 , wherein one or more amino acid residues of the heavy chain of the antibody is replaced with a cysteine residue.
28. The compound of claim 24 , wherein one or more amino acid residues of the Fc region of the antibody is replaced with a cysteine residue.
29. The compound of claim 27 , wherein the one or more amino acid residues of the heavy chain of the antibody is at position 157, 169 and/or 442 using EU numbering.
30. The compound of claim 24 , wherein D is linked to T by way of a cysteine residue.
31. The compound of claim 1 , wherein D is an amino-containing drug moiety, wherein the drug is connected to L 1 or X through the amino group.
32. The compound of claim 31 , wherein D is duocarmycin, dolastatin, tubulysin, doxorubicin (DOX), paclitaxel, or mitomycin C (MMC), or an amino derivative thereof.
33. The compound of claim 31 , wherein D is:
34. The compound of claim 1 , wherein -A-L 4 -L 3 -L 2 - is
35. The compound of claim 1 , wherein the
moiety is:
36. The compound of claim 1 , wherein the
moiety is:
37. The compound of claim 1 , wherein the
moiety is:
38. A pharmaceutical composition comprising a compound of claim 1 , or a salt or solvate or stereoisomer thereof; and a pharmaceutically acceptable carrier.
39. A kit comprising a compound of claim 1 , or a salt or solvate or stereoisomer thereof.
40. The kit of claim 39 , further comprising instructions for use in the treatment of cancer.
41. The compound of claim 1 , wherein T is a targeting moiety selected from the group consisting of: (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; and (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; and
the
moiety is selected from the group consisting of:
42. The compound of claim 1 , 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; and
the
moiety is selected from the group consisting of:
43. The compound of claim 1 , wherein T is an antibody comprising a heavy chain variable region comprising amino acids 1-119 of SEQ ID NO: 3 and a light chain variable region comprising amino acids 1-108 of SEQ ID NO: 4; and
the
moiety is selected from the group consisting of:
44. The compound of claim 1 , 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).
45. The compound of claim 1 , 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:3 and a light chain amino acid sequence of SEQ ID NO:4 (c5D7).
46. The compound of claim 1 , 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).
47. The compound of claim 1 , 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:3 and a light chain amino acid sequence of SEQ ID NO:4 (c5D7).
48. The compound of claim 1 , 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).
49. The compound of claim 1 , 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:3 and a light chain amino acid sequence of SEQ ID NO:4 (c5D7).
50. The compound of claim 4 , wherein L 1 is an aminobenzyloxycarbonyl linker.
51. The compound of claim 4 , wherein L 1 is selected from the group consisting of
52. (Ne The compound of claim 4 , wherein L 1 is selected from the group consisting of
53. The compound of claim 6 , wherein L 2 is an aminobenzyloxycarbonyl linker.
54. The compound of claim 6 , wherein L 2 is selected from
55. The compound of claim 1 , wherein L 3 is a peptide linker comprising at least one lysine or arginine residue.
56. The compound of claim 14 , wherein L 4 is L 4a -C(O), wherein L 4a is alkylene.
57. The compound of claim 1 , wherein A is selected from the group consisting of
wherein each Q 2 is independently NH or O.
58. The compound of claim 31 , wherein D is an amino derivative of duocarmycin selected from the group consisting of
59. The compound of claim 24 , wherein T is 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.
60. The compound of claim 24 , wherein T is 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.
61. The compound of claim 24 , 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.
62. The compound of claim 24 , wherein T is an antibody comprising a heavy chain variable region comprising amino acids 1-119 of SEQ ID NO: 3 and a light chain variable region comprising amino acids 1-108 of SEQ ID NO: 4.
63. A pharmaceutical composition comprising a compound of claim 41 , or a salt or solvate or stereoisomer thereof; and a pharmaceutically acceptable carrier.
64. A kit comprising a compound of claim 41 , or a salt or solvate or stereoisomer thereof.
65. A pharmaceutical composition comprising a compound of claim 46 , or a salt or solvate or stereoisomer thereof; and a pharmaceutically acceptable carrier.
66. A kit comprising a compound of claim 46 , or a salt or solvate or stereoisomer thereof.
67. The compound of claim 1 , wherein the compound is of the formula (IIIa):
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.
68. The compound of claim 1 , 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.
69. The compound of claim 1 , 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.
70. The compound of claim 1 , wherein the compound is of the formula (IIIa):
wherein p is 1, 2, 3 or 4, and wherein T is an antibody comprising a heavy chain variable region comprising amino acids 1-119 of SEQ ID NO: 3 and a light chain variable region comprising amino acids 1-108 of SEQ ID NO: 4.
71. The compound of claim 1 , 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 1-119 of SEQ ID NO: 3 and a light chain variable region comprising amino acids 1-108 of SEQ ID NO: 4.
72. The compound of claim 1 , 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 1-119 of SEQ ID NO: 3 and a light chain variable region comprising amino acids 1-108 of SEQ ID NO: 4.