Sulfatase-cleavable linkers for antibody-drug conjugates

Patent metadata

Field	Value
Publication number	US-11980668-B2
Application number	US-201917287792-A
Country	US
Kind code	B2
Filing date	Oct 23, 2019
Priority date	Nov 9, 2018
Publication date	May 14, 2024
Grant date	May 14, 2024

Abstract

The present disclosure provides antibody-drug conjugate structures, that include a cleavable linker having a sulfatase-cleavable moiety. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same.

First claim

What is claimed is:

1. A conjugate of formula (I):

wherein
Z is CR 4 or N;
R 1 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
R 2 and R 3 are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, or R 2 and R 3 are optionally cyclically linked to form a 5 or 6-membered heterocyclyl;
each R 4 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acyl amino, amino acyl, alkylamide, substituted alkylamide, sulfonyl, thioalkoxy, substituted thioalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
R 5 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl;
L 1 is a first linker;
L 2 is a second linker;
W 1 is a drug; and
W 2 is an antibody.

2. The conjugate of claim 1 , wherein the conjugate is of formula (Ia):

3. The conjugate of claim 1 , wherein the conjugate is of formula (Ib):

4. The conjugate of claim 1 , wherein the conjugate is of formula (Ic):

5. The conjugate of claim 1 , wherein the conjugate is of formula (Id):

6. The conjugate of claim 1 , wherein the conjugate is of formula (Ie):

7. The conjugate of claim 1 , wherein L 1 comprises:
-(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -,
wherein
a, b, c and d are each independently 0 or 1;
T 1 , T 2 , T 3 and T 4 are each independently selected from (C 1 -C 12 )alkyl, substituted (C 1 -C 12 )alkyl, (EDA)w, (PEG)n, (AA)p, —(CR 13 OH) m —, piperidin-4-amino (4AP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12;
V 1 , V 2 , V 3 and V 4 are each independently selected from the group consisting of a covalent bond, —CO—, —NR 15 —, —NR 15 (CH 2 ) q —, —NR 15 (C 6 H 4 )—, —CONR 15 —, —NR 15 CO—, —C(O)O—, —OC(O)—, —O—, —S—, —S(O)—, —SO 2 —, —SO 2 NR 15 —, —NR 15 SO 2 — and —P(O)OH—, wherein each q is an integer from 1 to 6;
each R 13 is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and
each R 15 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

8. The conjugate of claim 1 , wherein L 2 comprises:
-(T 5 -V 5 ) e -(T 6 -V 6 ) f -(T 7 -V 7 ) g -(T 8 -V 8 ) h -,
wherein
e, f, g and h are each independently 0 or 1;
T 5 , T 6 , T 7 and T 8 are each independently selected from (C 1 -C 12 )alkyl, substituted (C 1 -C 12 )alkyl, (EDA) w , (PEG) n , (AA) p , —(CR 13 OH) m —, piperidin-4-amino (4AP), an acetal group, a hydrazine, a disulfide, and an ester, wherein EDA is an ethylene diamine moiety, PEG is a polyethylene glycol, and AA is an amino acid residue, wherein each w is an integer from 1 to 20, each n is an integer from 1 to 30, each p is an integer from 1 to 20, and each m is an integer from 1 to 12;

V 5 , V 6 , V 7 and V 8 are each independently selected from the group consisting of a covalent bond, —CO—, —NR 15 —, —NR 15 (CH 2 ) q —, —NR 15 (C 6 H 4 )—, —CONR 15 —, —NR 15 CO—, —C(O)O—, —OC(O)—, —O—, —S—, —S(O)—, —SO 2 —, —SO 2 NR 15 —, —NR 15 SO 2 — and —P(O)OH—, wherein each q is an integer from 1 to 6;
each R 13 is independently selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl; and
each R 15 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, carboxyl, carboxyl ester, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl.

9. The conjugate of claim 7 , wherein:
T 1 is selected from a (C 1 -C 12 )alkyl and a substituted (C 1 -C 12 )alkyl;
T 2 , T 3 , and T 4 are each independently selected from (EDA) w , (PEG) n , (C 1 -C 12 )alkyl, substituted (C 1 -C 12 )alkyl, (AA) p , —(CR 13 OH) m —, 4-amino-piperidine (4AP), an acetal group, a hydrazine, and an ester; and
V 1 , V 2 , V 3 and V 4 are each independently selected from the group consisting of a covalent bond, —CO—, —NR 15 , —NR 15 (CH 2 ) q —, —NR 15 (C 6 H 4 )—, —CONR 15 —, —NR 15 CO—, —C(O)O—, —OC(O)—, —O—, —S—, —S(O)—, —SO 2 —, —SO 2 NR 15 —, —NR 15 SO 2 —, and —P(O)OH—;

wherein:
(PEG) n is

where n is an integer from 1 to 30;
EDA is an ethylene diamine moiety having the following structure:

where y is an integer from 1 to 6 and r is 0 or 1;
4-amino-piperidine (4AP) is

each R 12 and R 15 is independently selected from hydrogen, an alkyl, a substituted alkyl, a polyethylene glycol moiety, an aryl and a substituted aryl, wherein any two adjacent R 12 groups may be cyclically linked to form a piperazinyl ring; and
R 13 is selected from hydrogen, an alkyl, a substituted alkyl, an aryl, and a substituted aryl.

10. The conjugate of claim 7 , wherein:
T 1 is (C 1 -C 12 )alkyl and V 1 is —CO—;
T 2 is 4AP and V 2 is a covalent bond;
T 3 is (PEG) n and V 3 is —CONR 15 —; and
T 4 is (C 1 -C 12 )alkyl and V 4 is —CO—.

11. The conjugate of claim 1 , wherein the drug is an auristatin.

12. The conjugate of claim 1 , wherein the drug is a maytansine.

13. A pharmaceutical composition comprising:
a conjugate of claim 1 ; and
a pharmaceutically-acceptable excipient.

14. A method

Assignees

• Scherer Technologies Llc R P

Inventors

• Rabuka David
• Liu Junjie
• Chuprakov Stepan
• Kudirka Romas Alvydas

Classifications

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K47/6803 Primary

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K38/07

  Tetrapeptides · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title