Anti-folate receptor alpha (FRA) antibody-drug conjugates and methods of using thereof
The present disclosure provides anti-folate receptor alpha (FRA) antibody-drug conjugates comprising a hydrophilic self-immolative linker. The present disclosures further provide compositions and methods for treating cancers.
1. A compound of the formula (II):
or a salt or solvate or stereoisomer thereof; wherein:
D is a drug moiety;
T is a targeting moiety which is an antibody that specifically binds to a human folate receptor alpha (FRA);
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;
wherein:
(i) the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue; or
(ii) the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, wherein an amino acid residue at position 199 in the heavy chain constant region is replaced with a cysteine residue, and/or wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue;
wherein the numbering is according to the EU index of Kabat; and
wherein D is linked to T via a cysteine residue connected through the linker moiety
2. 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 which is an antibody that specifically binds to a human folate receptor alpha (FRA);
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;
wherein:
(i) the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue; or
(ii) the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, wherein an amino acid residue at position 199 in the heavy chain constant region is replaced with a cysteine residue, and/or wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue;
wherein the numbering is according to the EU index of Kabat; and
wherein D is linked to T via a cysteine residue connected through the linker moiety
3. The compound of claim 2 , wherein p is 1 to 4.
4. The compound of claim 2 , wherein L 1 is a bond.
5. The compound of claim 2 , wherein L 1 is a second self-immolative linker or a cyclization self-elimination linker.
6. The compound of claim 5 , wherein L 1 is an aminobenzyloxycarbonyl linker.
7. The compound of claim 5 , wherein L 1 is selected from the group consisting of
wherein n is 1 or 2.
8. The compound of claim 5 , wherein L 1 is selected from the group consisting of
9. The compound of claim 2 , wherein L 2 is a bond.
10. The compound of claim 4 , wherein L 2 is a second self-immolative linker.
11. The compound of claim 10 , wherein L 2 is an aminobenzyloxycarbonyl linker.
12. The compound of claim 10 , wherein L 2 is selected from
wherein n is 1 or 2.
13. The compound of claim 2 , wherein L 3 is a peptide linker of 1 to 10 amino acid residues.
14. The compound of claim 13 , wherein L 3 is a peptide linker of 2 to 4 amino acid residues.
15. The compound of claim 2 , wherein L 3 is a peptide linker comprising at least one lysine or arginine residue.
16. The compound of claim 2 , wherein L 3 is a peptide linker comprising an amino acid residue selected from lysine, D-lysine, citrulline, arginine, proline, histidine, ornithine and glutamine.
17. The compound of claim 2 , 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.
18. The compound of claim 13 , 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.
19. The compound of claim 18 , wherein L 3 is valine-citrulline.
20. The compound of claim 2 , wherein L 4 is a bond.
21. The compound of claim 2 , wherein L 4 is a spacer.
22. The compound of claim 21 , wherein the spacer is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
23. The compound of claim 21 , 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.
24. The compound of claim 21 , wherein L 4 is L 4a -C(O), wherein L 4a is polyalkylene glycol, alkylene, alkenylene, alkynylene, or polyamine.
25. The compound of claim 21 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyalkylene glycol.
26. The compound of claim 21 , wherein L 4 is L 4a -C(O), wherein L 4a is a polyethylene glycol.
27. The compound of claim 21 , 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.
28. The compound of claim 21 , wherein L 4 is L 4a -C(O), wherein L 4a is alkylene.
29. The compound of claim 2 , wherein A is selected from the group consisting of
wherein each Q 2 is NH or O, each q is independently an integer from 1 to 10, and each q 1 is independently an integer from 1 to 10.
30. The compound of claim 29 , 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.
31. The compound of claim 30 , wherein q is 2, 3, 4, or 5.
32. The compound of claim 2 , wherein A is selected from the group consisting of
wherein each Q 2 is independently NH or O.
33. The compound of claim 2 , wherein D is an amino-containing drug moiety, wherein the drug is connected to L 1 or X through the amino group.
34. The compound of claim 33 , wherein D is duocarmycin, dolastatin, tubulysin, doxorubicin (DOX), paclitaxel, or mitomycin C (MMC), or an amino derivative thereof.
35. The compound of claim 33 , wherein D is selected from the group consisting of
36. The compound of claim 33 , wherein D is:
37. The compound of claim 2 , wherein A L 4 L 3 L 2 is
38. The compound of claim 2 , wherein the
moiety is:
39. The compound of claim 2 , wherein the
moiety is:
40. The compound of claim 2 , wherein the
moiety is:
41. The compound of claim 2 , wherein the anti-folate receptor alpha (FRA) antibody is a humanized antibody, a chimeric antibody or a human antibody.
42. A pharmaceutical composition comprising a compound of claim 2 , or a salt or solvate or stereoisomer thereof; and a pharmaceutically acceptable carrier.
43. A kit comprising a compound of claim 2 , or a salt or solvate or stereoisomer thereof.
44. The compound of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, and wherein an amino acid residue at position 199 in the heavy chain constant region is replaced with a cysteine residue.
45. The compound of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, and wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue.
46. The compound of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, wherein an amino acid residue at position 199 in the heavy chain constant region is replaced with a cysteine residue, and wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue.
47. The compound of claim 2 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, and wherein an amino acid residue at position 199 in the heavy chain constant region is replaced with a cysteine residue.
48. The compound of claim 2 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, and wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue.
49. The compound of claim 2 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2, and a light chain comprising the amino acid sequence of SEQ ID NO: 3, wherein an amino acid residue at position 199 in the heavy chain constant region is replaced with a cysteine residue, and wherein an amino acid residue at position 201 in the light chain constant region is replaced with a cysteine residue.