Splicing modulator antibody-drug conjugates and methods of use
Linker-drug compounds and antibody-drug conjugates that bind to human oncology targets are disclosed. The linker-drug compounds and antibody-drug conjugates comprise a splicing modulator drug moiety. The disclosure further relates to methods and compositions for use in the treatment of neoplastic disorders by administering the antibody-drug conjugates provided herein. In an embodiment, the splicing modulator comprises a pladienolide or a pladienolide derivative.
1 . A compound of Formula (VI-A):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 9 are each independently chosen from absent, hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, —O—C(=O)—(C 1 -C 6 alkyl) groups, and —CD 3 ;
R 3 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 1 -C 6 alkylalkoxy groups, C 1 -C 6 alkylamino groups, C 1 -C 6 alkylcarboxylic acid groups, C 1 -C 6 alkylhydroxy groups, C 3 -C 8 cycloalkyl groups, benzyl groups, C 3 -C 8 heterocyclyl groups, and —O—C(=O)—(C 1 -C 6 alkyl) groups;
R 4 , R 5 , and R 8 are each independently chosen from hydrogen, hydroxyl, —O—(C 1 -C 6 alkyl) groups, —O—C(=O)—(C 1 -C 6 alkyl) groups, and C 1 -C 6 alkyl groups;
R 6 and R 7 are each independently chosen from hydrogen, —O—R 17 , —O—C(=O)—R 17 , —O—C(=O)—NR 15 R 16 , C 1 -C 6 alkyl groups, and —NR 15 R 16 ;
R 10 is chosen from hydrogen, C 1 -C 6 alkyl groups, —C(=O)—(C 1 -C 6 alkyl) groups, and —CD 3 ;
R 15 and R 16 are each independently chosen from hydrogen, R 17 , —C(=O)—R 17 , and —C(=O)—O—R 17 ;
R 17 is chosen from hydrogen, C 1 -C 6 alkyl groups, C 3 -C 8 cycloalkyl groups, benzyl groups, and C 3 -C 8 heterocyclyl groups; and
a is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
wherein R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently substituted with 0 to 3 groups independently chosen from halogens, hydroxyl, C 1 -C 6 alkyl groups, —O—(C 1 -C 6 alkyl) groups, —NR 15 R 16 , C 3 -C 8 cycloalkyl groups, C 1 -C 6 alkylhydroxy groups, C 1 -C 6 alkylalkoxy groups, benzyl groups, and C 3 -C 8 heterocyclyl groups;
wherein at least one of R 6 and R 7 is hydrogen;
wherein R 1 and R 9 cannot both be absent; and
L is a linker.
2 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is:
3 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound is:
4 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the linker L comprises a cleavable peptide moiety.
5 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the cleavable peptide moiety comprises valine-citrulline (Val-Cit), valine-alanine (Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), or alanine-alanine-asparagine (Ala-Ala-Asn).
6 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises at least one spacer unit comprising: (i) a polyethylene glycol moiety, (ii) an alkyl moiety, or (iii) a combination of (i) and (ii).
7 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises a maleimide (Mal) moiety.
8 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises maleimidocaproyl (MC).
9 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises p-aminobenzyl (pAB) or p-aminobenzyloxycarbonyl (pABC).
10 . The compound or pharmaceutically acceptable salt of claim 4 , wherein the linker L comprises MC-Val-Cit-pAB, MC-Val-Ala-pAB, MC-Glu-Val-Cit-pAB, MC-Ala-Ala-Asn-pAB, MC-Val-Cit-pABC, MC-Val-Ala-pABC, MC-Glu-Val-Cit-pABC, or MC-Ala-Ala-Asn-pABC.
11 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the linker L comprises a cleavable glucuronide moiety.
12 . The compound or pharmaceutically acceptable salt of claim 11 , wherein the cleavable glucuronide moiety is cleavable by a glucuronidase.
13 . The compound or pharmaceutically acceptable salt of claim 11 , wherein the linker L comprises MC-β-glucuronide-pAB or MC-β-glucuronide-pABC.
14 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the linker L is a non-cleavable linker comprising at least one spacer unit.
15 . The compound or pharmaceutically acceptable salt of claim 14 , wherein the linker L comprises a maleimide moiety.
16 . The compound or pharmaceutically acceptable salt of claim 15 , wherein the at least one spacer unit comprises (i) a polyethylene glycol moiety, (ii) an alkyl moiety, or (iii) a combination of (i) and (ii).
17 . The compound or pharmaceutically acceptable salt of claim 16 , wherein the linker L is chosen from:
and
18 . An antibody-drug conjugate of Formula (I):
Ab-(L-D) p (I)
wherein:
Ab is an antibody or antigen binding fragment which targets a neoplastic cell;
L-D is a compound or pharmaceutically acceptable salt of claim 1 ; and
p is an integer from 1 to 15.
19 . The antibody-drug conjugate of claim 18 , wherein L-D is a compound of formula:
or a pharmaceutically acceptable salt thereof.
20 . The antibody-drug conjugate of claim 18 , wherein L-D is a compound of formula:
or a pharmaceutically acceptable salt thereof.
21 . The antibody-drug conjugate of claim 18 , wherein the linker L comprises a cleavable peptide moiety.
22 . The antibody-drug conjugate of claim 21 , wherein the cleavable peptide moiety comprises valine-citrulline (Val-Cit), valine-alanine (Val-Ala), glutamic acid-valine-citrulline (Glu-Val-Cit), or alanine-alanine-asparagine (Ala-Ala-Asn).
23 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises at least one spacer unit comprising: (i) a polyethylene glycol moiety, (ii) an alkyl moiety, or (iii) a combination of (i) and (ii).
24 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises a maleimide (Mal) moiety.
25 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises maleimidocaproyl (MC).
26 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises p-aminobenzyl (pAB) or p-aminobenzyloxycarbonyl (pABC).
27 . The antibody-drug conjugate of claim 21 , wherein the linker L comprises MC-Val-Cit-pAB, MC-Val-Ala-pAB, MC-Glu-Val-Cit-pAB, MC-Ala-Ala-Asn-pAB, MC-Val-Cit-pABC, MC-Val-Ala-pABC, MC-Glu-Val-Cit-pABC, or MC-Ala-Ala-Asn-pABC.
28 . The antibody-drug conjugate of claim 18 , wherein the linker L comprises a cleavable glucuronide moiety.
29 . The antibody-drug conjugate of claim 28 , wherein the linker L comprises MC-β-glucuronide-pAB or MC-β-glucuronide-pABC.
30 . The antibody-drug conjugate of claim 21 , wherein p is an integer from 2 to 8.
31 . A pharmaceutical composition comprising the antibody-drug conjugate of claim 18 and a pharmaceutical acceptable carrier.
32 . A method of treating a subject having, or suspected of having, a neoplastic disorder, comprising administering a therapeutically effective amount of the antibody-drug conjugate of claim 18 .
33 . The method of claim 32 , wherein the neoplastic disorder is a leukemia, a lymphoma, or a myeloma.
34 . The method of claim 33 , wherein the myeloma is multiple myeloma.
35 . A method of reducing or inhibiting growth of a tumor in a subject having, or suspected of having, a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of the antibody-drug conjugate of claim 18 .