Antibody conjugates specific for mucin-1 and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2025152724-A1
Application number	US-202218291900-A
Country	US
Kind code	A1
Filing date	Oct 28, 2022
Priority date	Mar 23, 2022
Publication date	May 15, 2025
Grant date	—

Abstract

The present disclosure provides antibody conjugates (e.g., antibody-drug conjugates (ADCs)) specific for MUC1. The disclosure also encompasses methods of production of such conjugates, as well as methods of using the same. Also provided are compositions that include the ADC of the present disclosure, including in some instances, pharmaceutical compositions. In certain aspects, provided are methods of using the ADC that include administering to an individual having a cell proliferative disorder a therapeutically effective amount of the ADC of the present disclosure.

First claim

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;
L is a linker;
W 1 is a drug; and
W 2 is an anti-MUC1 antibody.

2 . The conjugate of claim 1 , wherein L comprises:
-(T 1 -V 1 ) a -(T 2 -V 2 ) b -(T 3 -V 3 ) c -(T 4 -V 4 ) d -(T 5 V 5 ) e -(T 6 -V 6 ) f -, wherein
a, b, c, d, e and f are each independently 0 or 1, wherein the sum of a, b, c, d, e and f is 1 to 6;
T 1 , T 2 , T 3 , T 4 , T 5 and T 6 are each independently selected from a covalent bond, (C 1 -C 12 )alkyl, substituted (C 1 -C 12 )alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w , (PEG) n , (AA) p , —(CR 13 OH) m —, 4-amino-piperidine (4AP), meta-amino-benzyloxy (MABO), meta-amino-benzyloxycarbonyl (MABC), para-amino-benzyloxy (PABO), para-amino-benzyloxycarbonyl (PABC), para-aminobenzyl (PAB), para-amino-benzylamino (PABA), para-amino-phenyl (PAP), para-hydroxy-phenyl (PHP), an acetal, 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 or an amino acid analog, 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 , V 4 , V 5 and V 6 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;
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.

3 . The conjugate of claim 2 , wherein:
T 1 is selected from a (C 1 -C 12 )alkyl and a substituted (C 1 -C 12 )alkyl; T 2 , T 3 , T 4 , T 5 and T 6 are each independently selected from a covalent bond, (C 1 -C 12 )alkyl, substituted (C 1 -C 12 )alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclyl, and substituted heterocyclyl, (EDA) w , (PEG) n , (AA) p , —(CR 13 OH) m —, 4-amino-piperidine (4AP), MABO, MABC, PABO, PABC, PAB, PABA, PAP, PHP, an acetal group, a hydrazine, and an ester; and V 1 , V 2 , V 3 , V 4 , V 5 and V 6 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

 and
each R 12 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.

4 . The conjugate of claim 2 , wherein MABO, MABC, PABO, PABC, PAB, PABA, PAP and PHP are each optionally substituted with a glycoside.

5 . The conjugate of any of claim 4 , wherein the glycoside is selected from a glucuronide, a galactoside, a glucoside, a mannoside, a fucoside, O-GlcNAc, and O-GalNAc.

6 . The conjugate of claim 2 ,
wherein:
T 1 is (C 1 -C 12 )alkyl and V 1 is —CO—;
T 2 is an amino acid analog and V 2 is —NH—;
T 3 is (PEG) n and V 3 is —CO—;
T 4 is AA and V 4 is absent;
T 5 is PABC and V 5 is absent; and
f is0.

7 . The conjugate of claim 1 , wherein the drug is monomethyl auristatin E (MMAE).

8 . The conjugate of claim 1 , wherein the conjugate has the structure:

9 . A conjugate of formula (II):

wherein:
Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from CR 24 , N and C-L B -W 12 , wherein at least one Z 1 , Z 2 , Z 3 and Z 4 is C-L B -W 12 ;
R 21 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 22 and R 23 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 22 and R 23 are optionally cyclically linked to form a 5 or 6-membered heterocyclyl;
each R 24 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;
L A is a first linker;
L B is a second linker;
W 11 is a first drug;
W 12 is a second drug; and
W 13 is an anti-MUC1 antibody.

Assignees

• Scherer Technologies Llc R P

Inventors

• Rabuka David
• Drake Penelope M
• Kim Yun Cheol
• Barfield Robyn M
• Bauzon Maxine
• Ogunkoya Ayodele
• Chuprakov Stepan

Classifications

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K16/2803

  against the immunoglobulin superfamily · CPC title